CN1413189A - Benzamidine derivatives - Google Patents

Benzamidine derivatives Download PDF

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CN1413189A
CN1413189A CN00817800A CN00817800A CN1413189A CN 1413189 A CN1413189 A CN 1413189A CN 00817800 A CN00817800 A CN 00817800A CN 00817800 A CN00817800 A CN 00817800A CN 1413189 A CN1413189 A CN 1413189A
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CN1293052C (en
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藤本光一
浅井史敏
松桥速生
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Sankyo Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/40—Oxygen atoms
    • C07D211/44—Oxygen atoms attached in position 4
    • C07D211/46—Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent in position 4
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

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Abstract

Benzamidine derivatives of general formula (I) or pharmacologically acceptable salts thereof exhibit excellent inhibitory activity against activated blood coagulation factor X and are useful as therapeutic or preventive drugs for diseases related to blood coagulation. In said formula, R<1> is hydrogen, halogeno, alkyl, or hydroxyl; R<2> is hydrogen, halogeno, or alkyl; R<3> is hydrogen, optionally substituted alkyl, aralkyl, optionally substituted alkanoyl, or optionally substituted alkylsulfonyl; R<4> and R<5> are each independently hydrogen, halogeno, optionally substituted alkyl, alkoxy, carbonyl, alkoxycarbonyl, or optionally substituted carbamoyl; and R<6> is substituted pyrrolidine or substituted piperidine.

Description

Benzamidine derivative
Technical field
The present invention relates to have acceptable salt on excellent inhibiting benzamidine derivative or its pharmacology to activating the blood coagulation X factor, contain described compound as purposes in the treatment of disorders of blood coagulation or prophylactic agent are made of the pharmaceutical composition that is used for the treatment of or prevent disorders of blood coagulation of effective constituent, described compound, by to this compounds for treating of warm-blooded animal drug treatment significant quantity or prevent the method for disorders of blood coagulation, and the method for making this compound.
Background technology
In recent years, because the aging of population, the causing circulatory disease that being accompanied by the age increases significantly increases.Wherein, the thrombotic diseases such as cerebral infarction, myocardial infarction and peripheral circulation disorders not only can cause death, and can cause the rear deterioration of patient, restriction life etc. to individual and social very big burden.Therefore, it is believed that, as the methods for the treatment of of this thrombotic diseases, it is more and more important that anticoagulant therapy will become from now on.
One of blood coagulation experience results from no matter which kind of stimulation and the multistage amplification process of the enzymatic reaction that activates, and it is that Fibrinogen occurs to limit and decomposes that the final zymoplasm that activates makes the solubility plasma proteins, and occurs by generating fibrinogen.Fibrinogen is insoluble protein, can form grumeleuse.This process is called the coagulation cascade reaction, and endogenous and exogenous two approach are arranged, and these two approach can make blood coagulation X factor activator when converging.The activation blood coagulation X factor of above such generation is a kind of enzyme that occupies critical positions in the coagulation cascade reaction, its final and formation complex body such as divalent calcium ion, phospholipid and activation blood coagulation accelerin, and make expeditiously prothrombin change into zymoplasm, thereby (for example promote the blood coagulation reaction, E.L.Smith, the people such as A.White, ' Principles of Biochemistry ': Mammalian Biochemistry (" biochemical theory ": mammiferous biological chemistry), the 7th edition, McGraw-Hill, Inc. (1983), etc.).
At present, the anticoagulant of use has warfarin (warfarin) and thrombin inhibitors.Although warfarin is widely used as orally active antithrombotic, this medicine is very restricted clinically, because its anticoagulant active is subject to the antagonism of vitamin K, and usually is subjected to diet or and with the impact of drug interaction (for example, Clin.Pharmacokinet.(clinical pharmacokinetics), 30, 416 (1996)).In addition, present thrombin inhibitors is accompanied by the side effect that its drug effect is also observed bleeding tendency, therefore, wishes the anticoagulant that exploitation makes new advances.The blood coagulation X factor that activates is directly connected to the formation of zymoplasm, and known its inhibitor demonstrates blood coagulation resisting function, therefore, it is believed that this X factor inhibitors (for example, is expected to become new anticoagulant Drugs, 49, 856 (1995) etc.).
As the activation blood coagulation X factor inhibitors of competitive antagonism type, the flat 5-208946 of Japanese Patent Application Laid-Open (EP540051), WO96/16940 (EP798295) or WO00/47553 disclose aromatic amidine analog derivative or amidino groups naphthyl derivatives.In addition, WO98/31661 (EP976722) discloses such as N-(4-(1-acetimidoyl-4-piperidines oxygen base) phenyl)-benzamidine derivatives such as N-(2-(3-amidino groups) phenoxy group) sulphonamide acetic acid two (trifluoroacetate).
The disclosure of an invention content
The present inventors have the compound that the excellent activation blood coagulation X factor suppresses activity in order to develop, for many years the pharmacologically active of various benzamidine derivatives carried out research with keen determination, found that the benzamidine derivative with specific structure has the excellent activation blood coagulation X factor and suppresses active, but there is not to cause the antitrypsic activity of side effect, therefore can be used as prophylactic agent or the curative (especially curative) of disorders of blood coagulation, so finished the present invention.
The present invention relates to have acceptable salt on excellent inhibiting benzamidine derivative or its pharmacology to activating the blood coagulation X factor, contain described compound as purposes in the treatment of disorders of blood coagulation or prophylactic agent are made of the pharmaceutical composition that is used for the treatment of or prevent disorders of blood coagulation of effective constituent, described compound, by to this compounds for treating of warm-blooded animal drug treatment significant quantity or prevent the method for disorders of blood coagulation, and the method for making this compound.
Benzamidine derivative of the present invention has following general formula (I)
Figure A0081780000091
In the formula:
R 1Represent hydrogen atom, halogen atom, C 1-C 6Alkyl or hydroxyl;
R 2Represent hydrogen atom, halogen atom or C 1-C 6Alkyl;
R 3Represent hydrogen atom; C 1-C 6Alkyl; By hydroxyl, carboxyl or (C 1-C 6Alkoxyl group) C of carbonyl substituted 1-C 6Alkyl; Group shown in the general formula (II)
Figure A0081780000101
R in the formula 7Represent C 1-C 6Alkyl, m and n are identical or different, represent 1～6 integer; C 7-C 15Aralkyl; C 1-C 6Alkanoyl; Hydroxyl C 2-C 6Alkanoyl; C 1-C 6Alkyl sulphonyl; Or by (C 1-C 6Alkoxyl group) C of carbonyl or carboxyl substituted 1-C 6Alkyl sulphonyl;
R 4And R 5Identical or different, represent hydrogen atom, halogen atom, C 1-C 6Alkyl, halo C 1-C 6Alkyl, C 1-C 6Alkoxyl group, carboxyl, (C 1-C 6Alkoxyl group) carbonyl, formamyl, (C 1-C 6Alkyl) formamyl or two (C 1-C 6Alkyl) formamyl; And
R 6Represent 1-acetimidoyl pyrrolidin-3-yl or 1-acetimidoyl piperidin-4-yl.
In addition, the effective constituent of the pharmaceutical composition for the treatment of of the present invention or prevention disorders of blood coagulation is the benzamidine derivative with general formula (I).
In above-mentioned general formula (I), R 1" halogen atom " in the definition can be for example fluorine atom, chlorine atom, bromine atoms or iodine atom, preferably fluorine atom, chlorine atom or bromine atoms, more preferably fluorine atom or chlorine atom, particularly preferably fluorine atom.
At above-mentioned R 1" (C in the definition 1-C 6Alkyl) " be the straight or branched alkyl of for example 1～6 carbon atom; such as methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl, amyl group, isopentyl, 2-methyl butyl, neo-pentyl, 1-ethyl propyl, hexyl, 4-methyl amyl, 3-methyl amyl, 2-methyl amyl, 1-methyl amyl, 3; 3-dimethylbutyl, 2; 2-dimethylbutyl, 1; 1-dimethylbutyl, 1; 2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl or 2-ethyl-butyl, preferably C 1-C 4Alkyl, more preferably methyl or ethyl, particularly preferably methyl.
At above-mentioned R 2" halogen atom " in the definition can be for example with above-mentioned R 1Middle definition identical, preferably fluorine atom or chlorine atom, particularly preferably fluorine atom.
At above-mentioned R 2" C in the definition 1-C 6Alkyl " can be for example with above-mentioned R 1Middle definition identical, preferably C 1-C 4Alkyl, more preferably methyl or ethyl, particularly preferably methyl.
At above-mentioned R 3" C in the definition 1-C 6Alkyl " and " by hydroxyl, carboxyl or (C 1-C 6Alkoxyl group) C of carbonyl substituted 1-C 6Alkyl " in " C 1-C 6Alkyl " part can be for example with above-mentioned R 1Middle definition identical." C 1-C 6Alkyl " C preferably 1-C 4Alkyl is more preferably methyl, ethyl or sec.-propyl, most preferably is sec.-propyl.On the other hand, " by hydroxyl, carboxyl or (C 1-C 6Alkoxyl group) C of carbonyl substituted 1-C 6Alkyl " in " C 1-C 6Alkyl " part C preferably 1-C 4Alkyl is more preferably methyl or ethyl, particularly preferably is methyl.
At above-mentioned R 3In the definition " by hydroxyl, carboxyl or (C 1-C 6Alkoxyl group) C of carbonyl substituted 1-C 6Alkyl " substituting group and " by (C 1-C 6Alkoxyl group) C of carbonyl or carboxyl substituted 1-C 6Alkyl sulphonyl " substituent definition in " (C 1-C 6Alkoxyl group) carbonyl " can be for example to be connected on the straight or branched alkoxyl group that contains 1-6 carbon atom and the group that forms by carbonyl; such as methoxycarbonyl; ethoxycarbonyl; the third oxygen carbonyl; isopropyl oxygen carbonyl; butoxy carbonyl, isobutyl boc, secondary butoxy carbonyl, tertbutyloxycarbonyl, penta oxygen carbonyl, isoamyl oxygen carbonyl, 2-methyl butoxy carbonyl, new penta oxygen carbonyl, 1-ethyl the third oxygen carbonyl, own oxygen carbonyl, 4-methylpent oxygen carbonyl, 3-methylpent oxygen carbonyl, 2-methylpent oxygen carbonyl, 1-methylpent oxygen carbonyl, 3,3-dimethyl butoxy carbonyl, 2,2-dimethyl butoxy carbonyl, 1,1-dimethyl butoxy carbonyl, 1,2-dimethyl butoxy carbonyl, 1,3-dimethyl butoxy carbonyl, 2,3-dimethyl butoxy carbonyl or 2-ethyl butoxy carbonyl, preferably (C 1-C 4Alkoxyl group) carbonyl is more preferably methoxycarbonyl or ethoxycarbonyl, particularly preferably is ethoxycarbonyl.
At above-mentioned R 3In the definition " by hydroxyl, carboxyl or (C 1-C 6Alkoxyl group) C of carbonyl substituted 1-C 6Alkyl " can be for example by hydroxyl, carboxyl or (C 1-C 6Alkoxyl group) the above-mentioned C of carbonyl substituted 1-C 6Alkyl, such as methylol, the 1-hydroxyethyl, the 2-hydroxyethyl, the 1-hydroxypropyl, the 2-hydroxypropyl, the 3-hydroxypropyl, the 1-hydroxybutyl, the 2-hydroxybutyl, the 3-hydroxybutyl, the 4-hydroxybutyl, 5-hydroxyl amyl group or 6-hydroxyl hexyl, carboxymethyl, the 1-carboxy ethyl, the 2-carboxy ethyl, 1-carboxyl propyl group, 2-carboxyl propyl group, 3-carboxyl propyl group, the 1-carboxybutyl, the 2-carboxybutyl, the 3-carboxybutyl, the 4-carboxybutyl, 5-carboxy pentyl or 6-carboxyl hexyl, the methoxycarbonyl methyl, ethoxycarbonylmethyl group, the third oxygen carbonyl methyl, isopropyl oxygen carbonyl methyl, the butoxy carbonyl methyl, the isobutyl boc methyl, the secondary butoxy carbonyl methyl, the tertiary butyloxycarbonyl ylmethyl, penta oxygen carbonyl methyl, isoamyl oxygen carbonyl methyl, 2-methyl butoxy carbonyl methyl, new penta oxygen carbonyl methyl, 1-ethyl the third oxygen carbonyl methyl, own oxygen carbonyl methyl, 4-methylpent oxygen carbonyl methyl, 3-methylpent oxygen carbonyl methyl, 2-methylpent oxygen carbonyl methyl, 1-methylpent oxygen carbonyl methyl, 3,3-dimethyl butoxy carbonyl methyl, 2,2-dimethyl butoxy carbonyl methyl, 1,1-dimethyl butoxy carbonyl methyl, 1,2-dimethyl butoxy carbonyl methyl, 1,3-dimethyl butoxy carbonyl methyl, 2,3-dimethyl butoxy carbonyl methyl, 2-ethyl butoxy carbonyl methyl, 1-(methoxycarbonyl) ethyl, 1-(ethoxycarbonyl) ethyl, 1-(the third oxygen carbonyl) ethyl, 1-(isopropyl oxygen carbonyl) ethyl, 1-(butoxy carbonyl) ethyl, 1-(isobutyl boc) ethyl, 1-(secondary butoxy carbonyl) ethyl, 1-(tertbutyloxycarbonyl) ethyl, 1-(penta oxygen carbonyl) ethyl, 1-(isoamyl oxygen carbonyl) ethyl, 1-(2-methyl butoxy carbonyl) ethyl, 1-(new penta oxygen carbonyl) ethyl, 1-(1-ethyl the third oxygen carbonyl) ethyl, 1-(own oxygen carbonyl) ethyl, 1-(4-methylpent oxygen carbonyl) ethyl, 1-(3-methylpent oxygen carbonyl) ethyl, 1-(2-methylpent oxygen carbonyl) ethyl, 1-(1-methylpent oxygen carbonyl) ethyl, 1-(3,3-dimethyl butoxy carbonyl) ethyl, 1-(2,2-dimethyl butoxy carbonyl) ethyl, 1-(1,1-dimethyl butoxy carbonyl) ethyl, 1-(1,2-dimethyl butoxy carbonyl) ethyl, 1-(1,3-dimethyl butoxy carbonyl) ethyl, 1-(2,3-dimethyl butoxy carbonyl) ethyl, 1-(2-ethyl butoxy carbonyl) ethyl, 2-(methoxycarbonyl) ethyl, 2-(ethoxycarbonyl) ethyl, 2-(the third oxygen carbonyl) ethyl, 2-(isopropyl oxygen carbonyl) ethyl, 2-(butoxy carbonyl) ethyl, 2-(isobutyl boc) ethyl, 2-(secondary butoxy carbonyl) ethyl, 2-(tertbutyloxycarbonyl) ethyl, 2-(penta oxygen carbonyl) ethyl, 2-(isoamyl oxygen carbonyl) ethyl, 2-(2-methyl butoxy carbonyl) ethyl, 2-(new penta oxygen carbonyl) ethyl, 2-(1-ethyl the third oxygen carbonyl) ethyl, 2-(own oxygen carbonyl) ethyl, 2-(4-methylpent oxygen carbonyl) ethyl, 2-(3-methylpent oxygen carbonyl) ethyl, 2-(2-methylpent oxygen carbonyl) ethyl, 2-(1-methylpent oxygen carbonyl) ethyl, 2-(3,3-dimethyl butoxy carbonyl) ethyl, 2-(2,2-dimethyl butoxy carbonyl) ethyl, 2-(1,1-dimethyl butoxy carbonyl) ethyl, 2-(1,2-dimethyl butoxy carbonyl) ethyl, 2-(1,3-dimethyl butoxy carbonyl) ethyl, 2-(2,3-dimethyl butoxy carbonyl) ethyl, 2-(2-ethyl butoxy carbonyl) ethyl, 3-(methoxycarbonyl) propyl group, 3-(ethoxycarbonyl) propyl group, 3-(the third oxygen carbonyl) propyl group, 3-(isopropyl oxygen carbonyl) propyl group, 3-(butoxy carbonyl) propyl group, 3-(isobutyl boc) propyl group, 3-(secondary butoxy carbonyl) propyl group, 3-(tertbutyloxycarbonyl) propyl group, 3-(penta oxygen carbonyl) propyl group, 3-(isoamyl oxygen carbonyl) propyl group, 3-(own oxygen carbonyl) propyl group, 4-(methoxycarbonyl) butyl, 4-(ethoxycarbonyl) butyl, 4-(the third oxygen carbonyl) butyl, 4-(isopropyl oxygen carbonyl) butyl, 4-(butoxy carbonyl) butyl, 4-(isobutyl boc) butyl, (4-secondary butoxy carbonyl) butyl, 4-(tertbutyloxycarbonyl) butyl, 4-(penta oxygen carbonyl) butyl, 4-(isoamyl oxygen carbonyl) butyl, 4-(own oxygen carbonyl) butyl, 5-(methoxycarbonyl) amyl group, 5-(ethoxycarbonyl) amyl group, 5-(the third oxygen carbonyl) amyl group, 5-(butoxy carbonyl) amyl group, 5-(penta oxygen carbonyl) amyl group, 5-(own oxygen carbonyl) amyl group, 6-(methoxycarbonyl) hexyl, 6-(ethoxycarbonyl) hexyl, 6-(the third oxygen carbonyl) hexyl, 6-(butoxy carbonyl) hexyl, 6-(penta oxygen carbonyl) hexyl or 6-(own oxygen carbonyl) hexyl, preferably hydroxyl C 1-C 4Alkyl, carboxyl C 1-C 4Alkyl or (C 1-C 4Alkoxyl group) carbonyl (C 1-C 4Alkyl), be more preferably hydroxyl C 1-C 4Alkyl or (C 1-C 4Alkoxyl group) carbonyl methyl, be more preferably again 2-hydroxyethyl, carboxymethyl, methoxycarbonyl methyl, ethoxycarbonylmethyl group, the third oxygen carbonyl methyl or butoxy carbonyl methyl, particularly preferably being 2-hydroxyethyl, carboxymethyl, methoxycarbonyl methyl or ethoxycarbonylmethyl group, most preferably is carboxymethyl or ethoxycarbonylmethyl group.
In above-mentioned general formula (II), R 7" C in the definition 1-C 6Alkyl " can be for example with R 1Middle definition identical, preferably C 1-C 4Alkyl is more preferably methyl or ethyl, particularly preferably ethyl.
In above-mentioned, m is the integer of 1-4 preferably, and more preferably 1 or 2.
In above-mentioned, n is the integer of 1-4 preferably, and more preferably 1 or 2.
In above-mentioned general formula (I), R 3" C in the definition 7-C 15Aralkyl " can be for example by 1 or 2 above-mentioned " C that contains the aromatic hydrocarbyl replacement of 6-14 carbon atom 1-C 6Alkyl " such as benzyl, menaphthyl, indenyl methyl, phenanthryl methyl, anthryl methyl, diphenyl methyl, styroyl, naphthalene ethyl, hydrocinnamyl, naphthalene propyl group, benzene butyl, naphthalene butyl, benzene amyl group, naphthalene amyl group or benzene hexyl; preferably benzyl, menaphthyl, diphenyl methyl or styroyl; being more preferably benzyl or styroyl, particularly preferably is benzyl.
At above-mentioned R 3" C in the definition 1-C 6Alkanoyl " can be the alkanoyl that for example contains the straight or branched of 1-6 carbon atom, such as formyl radical, ethanoyl, propionyl, butyryl radicals, isobutyryl, valeryl, pentanoyl, isovaleryl or caproyl, preferably C 1-C 4Alkanoyl is more preferably formyl radical or ethanoyl, particularly preferably is ethanoyl.
At above-mentioned R 3" hydroxyl C in the definition 2-C 6Alkanoyl " can be the above-mentioned " C that is for example replaced by hydroxyl 1-C 6Alkanoyl "; such as hydroxyacetyl, 2-hydroxyl propionyl, 3-hydroxyl propionyl, 4-maloyl group, 5-hydroxyl pentanoyl or 6-hydroxyl caproyl; preferably hydroxyacetyl, 3-hydroxyl propionyl or 4-maloyl group, particularly preferably be hydroxyacetyl.
At above-mentioned R 3" C in the definition 1-C 6Alkyl sulphonyl " can be for example by above-mentioned " C 1-C 6Alkyl " be connected on the alkylsulfonyl and the group that forms; such as methylsulfonyl, ethylsulfonyl, the third alkylsulfonyl, isopropyl alkylsulfonyl, fourth alkylsulfonyl, isobutyl alkylsulfonyl, penta alkylsulfonyl, isoamyl alkylsulfonyl, new penta alkylsulfonyl, own alkylsulfonyl or dissident's alkylsulfonyl; preferably methylsulfonyl, ethylsulfonyl, the third alkylsulfonyl, fourth alkylsulfonyl, penta alkylsulfonyl or own alkylsulfonyl; being more preferably methylsulfonyl, ethylsulfonyl or fourth alkylsulfonyl, particularly preferably is ethylsulfonyl.
At above-mentioned R 3" quilt (C in the definition 1-C 6Alkoxyl group) C of carbonyl or carboxyl substituted 1-C 6Alkyl sulphonyl " can be for example to be selected from above-mentioned (C by 1 1-C 6Alkoxyl group) substituting group of carbonyl or carboxyl is connected to above-mentioned C 1-C 6On the alkyl sulphonyl and the group that forms; such as the methoxycarbonyl methylsulfonyl; the ethoxycarbonyl methylsulfonyl; the third oxygen carbonyl methylsulfonyl; isopropyl oxygen carbonyl methylsulfonyl; the butoxy carbonyl methylsulfonyl; the isobutyl boc methylsulfonyl; the secondary butoxy carbonyl methylsulfonyl; the tertbutyloxycarbonyl methylsulfonyl; penta oxygen carbonyl methylsulfonyl; isoamyl oxygen carbonyl methylsulfonyl; 2-methyl butoxy carbonyl methylsulfonyl; new penta oxygen carbonyl methylsulfonyl; 1-ethyl the third oxygen carbonyl methylsulfonyl; own oxygen carbonyl methylsulfonyl; 4-methylpent oxygen carbonyl methylsulfonyl; 3-methylpent oxygen carbonyl methylsulfonyl; 2-methylpent oxygen carbonyl methylsulfonyl; 1-methylpent oxygen carbonyl methylsulfonyl; 3; 3-dimethyl butoxy carbonyl methylsulfonyl; 2; 2-dimethyl butoxy carbonyl methylsulfonyl; 1; 1-dimethyl butoxy carbonyl methylsulfonyl; 1; 2-dimethyl butoxy carbonyl methylsulfonyl; 1; 3-dimethyl butoxy carbonyl methylsulfonyl; 2; 3-dimethyl butoxy carbonyl methylsulfonyl or 2-ethyl butoxy carbonyl methylsulfonyl; 1-(methoxycarbonyl) ethylsulfonyl; 1-(ethoxycarbonyl) ethylsulfonyl; 1-(the third oxygen carbonyl) ethylsulfonyl; 1-(isopropyl oxygen carbonyl) ethylsulfonyl; 1-(butoxy carbonyl) ethylsulfonyl; 1-(isobutyl boc) ethylsulfonyl; 1-(secondary butoxy carbonyl) ethylsulfonyl; 1-(tertbutyloxycarbonyl) ethylsulfonyl; 1-(penta oxygen carbonyl) ethylsulfonyl; 1-(isoamyl oxygen carbonyl) ethylsulfonyl; 1-(2-methyl butoxy carbonyl) ethylsulfonyl; 1-(new penta oxygen carbonyl) ethylsulfonyl; 1-(1-ethyl the third oxygen carbonyl) ethylsulfonyl; 1-(own oxygen carbonyl) ethylsulfonyl; 1-(4-methylpent oxygen carbonyl) ethylsulfonyl; 1-(3-methylpent oxygen carbonyl) ethylsulfonyl; 1-(2-methylpent oxygen carbonyl) ethylsulfonyl; 1-(1-methylpent oxygen carbonyl) ethylsulfonyl; 1-(3; 3-dimethyl butoxy carbonyl) ethylsulfonyl; 1-(2; 2-dimethyl butoxy carbonyl) ethylsulfonyl; 1-(1; 1-dimethyl butoxy carbonyl) ethylsulfonyl; 1-(1; 2-dimethyl butoxy carbonyl) ethylsulfonyl; 1-(1; 3-dimethyl butoxy carbonyl) ethylsulfonyl; 1-(2; 3-dimethyl butoxy carbonyl) ethylsulfonyl; 1-(2-ethyl butoxy carbonyl) ethylsulfonyl; 2-(methoxycarbonyl) ethylsulfonyl; 2-(ethoxycarbonyl) ethylsulfonyl; 2-(the third oxygen carbonyl) ethylsulfonyl; 2-(isopropyl oxygen carbonyl) ethylsulfonyl; 2-(butoxy carbonyl) ethylsulfonyl; 2-(isobutyl boc) ethylsulfonyl; 2-(secondary butoxy carbonyl) ethylsulfonyl; 2-(tertbutyloxycarbonyl) ethylsulfonyl; 2-(penta oxygen carbonyl) ethylsulfonyl; 2-(isoamyl oxygen carbonyl) ethylsulfonyl; 2-(2-methyl butoxy carbonyl) ethylsulfonyl; 2-(new penta oxygen carbonyl) ethylsulfonyl; 2-(1-ethyl the third oxygen carbonyl) ethylsulfonyl; 2-(own oxygen carbonyl) ethylsulfonyl; 2-(4-methylpent oxygen carbonyl) ethylsulfonyl; 2-(3-methylpent oxygen carbonyl) ethylsulfonyl; 2-(2-methylpent oxygen carbonyl) ethylsulfonyl; 2-(1-methylpent oxygen carbonyl) ethylsulfonyl; 2-(3; 3-dimethyl butoxy carbonyl) ethylsulfonyl; 2-(2; 2-dimethyl butoxy carbonyl) ethylsulfonyl; 2-(1; 1-dimethyl butoxy carbonyl) ethylsulfonyl; 2-(1; 2-dimethyl butoxy carbonyl) ethylsulfonyl; 2-(1; 3-dimethyl butoxy carbonyl) ethylsulfonyl; 2-(2; 3-dimethyl butoxy carbonyl) ethylsulfonyl; 2-(2-ethyl butoxy carbonyl) ethylsulfonyl; 1-(methoxycarbonyl) the third alkylsulfonyl; 1-(ethoxycarbonyl) the third alkylsulfonyl; 1-(the third oxygen carbonyl) the third alkylsulfonyl; 1-(butoxy carbonyl) the third alkylsulfonyl; 1-(penta oxygen carbonyl) the third alkylsulfonyl; 1-(own oxygen carbonyl) the third alkylsulfonyl; 2-(methoxycarbonyl) the third alkylsulfonyl; 2-(ethoxycarbonyl) the third alkylsulfonyl; 2-(the third oxygen carbonyl) the third alkylsulfonyl; 2-(butoxy carbonyl) the third alkylsulfonyl; 2-(penta oxygen carbonyl) the third alkylsulfonyl; 2-(own oxygen carbonyl) the third alkylsulfonyl; 3-(methoxycarbonyl) the third alkylsulfonyl; 3-(ethoxycarbonyl) the third alkylsulfonyl; 3-(the third oxygen carbonyl) the third alkylsulfonyl; 3-(isopropyl oxygen carbonyl) the third alkylsulfonyl; 3-(butoxy carbonyl) the third alkylsulfonyl; 3-(isobutyl boc) the third alkylsulfonyl; 3-(secondary butoxy carbonyl) the third alkylsulfonyl; 3-(tertbutyloxycarbonyl) the third alkylsulfonyl; 3-(penta oxygen carbonyl) the third alkylsulfonyl; 3-(isoamyl oxygen carbonyl) the third alkylsulfonyl; 3-(2-methyl butoxy carbonyl) the third alkylsulfonyl; 3-(new penta oxygen carbonyl) the third alkylsulfonyl; 3-(1-ethyl the third oxygen carbonyl) the third alkylsulfonyl; 3-(own oxygen carbonyl) the third alkylsulfonyl; 3-(4-methylpent oxygen carbonyl) the third alkylsulfonyl; 3-(3-methylpent oxygen carbonyl) the third alkylsulfonyl; 3-(2-methylpent oxygen carbonyl) the third alkylsulfonyl; 3-(1-methylpent oxygen carbonyl) the third alkylsulfonyl; 3-(3; 3-dimethyl butoxy carbonyl) the third alkylsulfonyl; 3-(2; 2-dimethyl butoxy carbonyl) the third alkylsulfonyl; 3-(1; 1-dimethyl butoxy carbonyl) the third alkylsulfonyl; 3-(1; 2-dimethyl butoxy carbonyl) the third alkylsulfonyl; 3-(1; 3-dimethyl butoxy carbonyl) the third alkylsulfonyl; 3-(2; 3-dimethyl butoxy carbonyl) the third alkylsulfonyl; 3-(2-ethyl butoxy carbonyl) the third alkylsulfonyl; 2-methoxycarbonyl-1-methyl ethylsulfonyl; 2-ethoxycarbonyl-1-methyl ethylsulfonyl; 2-the third oxygen carbonyl-1-methyl ethylsulfonyl; 2-butoxy carbonyl-1-methyl ethylsulfonyl; 1-(methoxycarbonyl) fourth alkylsulfonyl; 1-(ethoxycarbonyl) fourth alkylsulfonyl; 1-(the third oxygen carbonyl) fourth alkylsulfonyl; 1-(butoxy carbonyl) fourth alkylsulfonyl; 1-(penta oxygen carbonyl) fourth alkylsulfonyl; 1-(own oxygen carbonyl) fourth alkylsulfonyl; 2-(methoxycarbonyl) fourth alkylsulfonyl; 2-(ethoxycarbonyl) fourth alkylsulfonyl; 2-(the third oxygen carbonyl) fourth alkylsulfonyl; 2-(butoxy carbonyl) fourth alkylsulfonyl; 2-(penta oxygen carbonyl) fourth alkylsulfonyl; 2-(own oxygen carbonyl) fourth alkylsulfonyl; 3-(methoxycarbonyl) fourth alkylsulfonyl; 3-(ethoxycarbonyl) fourth alkylsulfonyl; 3-(the third oxygen carbonyl) fourth alkylsulfonyl; 3-(butoxy carbonyl) fourth alkylsulfonyl; 3-(penta oxygen carbonyl) fourth alkylsulfonyl; 3-(own oxygen carbonyl) fourth alkylsulfonyl; 4-(methoxycarbonyl) fourth alkylsulfonyl; 4-(ethoxycarbonyl) fourth alkylsulfonyl; 4-(the third oxygen carbonyl) fourth alkylsulfonyl; 4-(isopropyl oxygen carbonyl) fourth alkylsulfonyl; 4-(butoxy carbonyl) fourth alkylsulfonyl; 4-(isobutyl boc) fourth alkylsulfonyl; 4-(secondary butoxy carbonyl) fourth alkylsulfonyl; 4-(tertbutyloxycarbonyl) fourth alkylsulfonyl; 4-(penta oxygen carbonyl) fourth alkylsulfonyl; 4-(isoamyl oxygen carbonyl) fourth alkylsulfonyl; 4-(2-methyl butoxy carbonyl) fourth alkylsulfonyl; 4-(new penta oxygen carbonyl) fourth alkylsulfonyl; 4-(1-ethyl the third oxygen carbonyl) fourth alkylsulfonyl; 4-(own oxygen carbonyl) fourth alkylsulfonyl; 4-(4-methylpent oxygen carbonyl) fourth alkylsulfonyl; 4-(3-methylpent oxygen carbonyl) fourth alkylsulfonyl; 4-(2-methylpent oxygen carbonyl) fourth alkylsulfonyl; 4-(1-methylpent oxygen carbonyl) fourth alkylsulfonyl; 4-(3; 3-dimethyl butoxy carbonyl) fourth alkylsulfonyl; 4-(2; 2-dimethyl butoxy carbonyl) fourth alkylsulfonyl; 4-(1; 1-dimethyl butoxy carbonyl) fourth alkylsulfonyl; 4-(1; 2-dimethyl butoxy carbonyl) fourth alkylsulfonyl; 4-(1; 3-dimethyl butoxy carbonyl) fourth alkylsulfonyl; 4-(2; 3-dimethyl butoxy carbonyl) fourth alkylsulfonyl; 4-(2-ethyl butoxy carbonyl) fourth alkylsulfonyl; 3-methoxycarbonyl-2-methyl-prop alkylsulfonyl; 3-ethoxycarbonyl-2-methyl the third alkylsulfonyl; 5-(methoxycarbonyl) penta alkylsulfonyl; 5-(ethoxycarbonyl) penta alkylsulfonyl; 5-(the third oxygen carbonyl) penta alkylsulfonyl; 5-(butoxy carbonyl) penta alkylsulfonyl; 5-(penta oxygen carbonyl) penta alkylsulfonyl; 5-(own oxygen carbonyl) penta alkylsulfonyl; the own alkylsulfonyl of 6-(methoxycarbonyl); the own alkylsulfonyl of 6-(ethoxycarbonyl); the own alkylsulfonyl of 6-(the third oxygen carbonyl); the own alkylsulfonyl of 6-(butoxy carbonyl); the own alkylsulfonyl of 6-(penta oxygen carbonyl); the own alkylsulfonyl of 6-(own oxygen carbonyl); 2-carboxyl ethylsulfonyl; 3-carboxyl the third alkylsulfonyl; 2-carboxyl-1-methyl ethylsulfonyl; 4-carboxyl fourth alkylsulfonyl; 3-carboxyl-2-methyl-prop alkylsulfonyl; 5-carboxyl penta alkylsulfonyl or the own alkylsulfonyl of 6-carboxyl are preferably by (C 1-C 4Alkoxyl group) C of carbonyl or carboxyl substituted 1-C 4Alkyl sulphonyl is more preferably by (C 1-C 4Alkoxyl group) methylsulfonyl of carbonyl or carboxyl substituted or ethylsulfonyl; more preferably methoxycarbonyl methylsulfonyl, ethoxycarbonyl methylsulfonyl, carboxyl methylsulfonyl, 2-methoxycarbonyl ethylsulfonyl, 2-ethoxycarbonyl ethylsulfonyl or 2-carboxyl ethylsulfonyl particularly preferably are ethoxycarbonyl methylsulfonyl or carboxyl methylsulfonyl again.
At above-mentioned R 4And R 5" halogen atom " in the definition can be and above-mentioned R 1Middle definition identical, preferably fluorine atom, chlorine atom or bromine atoms, more preferably fluorine atom or chlorine atom, particularly preferably chlorine atom.
At above-mentioned R 4And R 5" C in the definition 1-C 6Alkyl " can be and R 1Middle definition identical, preferably C 1-C 4Alkyl is more preferably methyl or ethyl, particularly preferably methyl.
At above-mentioned R 4And R 5" halo C in the definition 1-C 6Alkyl " can be the above-mentioned " C that is for example replaced by 1-5 above-mentioned " halogen atom " 1-C 5Alkyl "; such as methyl fluoride, difluoromethyl, trifluoromethyl, 2-fluoro ethyl, 2; 2-two fluoro ethyls, 2; 2; 2-trifluoroethyl, pentafluoroethyl group, 3-fluoropropyl, 4-fluorine butyl, 6-fluorine hexyl, chloromethyl, 2-chloroethyl, 3-chloropropyl, 4-chlorobutyl, brooethyl, 3-bromopropyl, dibromo amyl group, iodomethyl or 2-fluoro-1-chloroethyl, preferably by 1-3 C that is selected from the halogen atom replacement of fluorine atom and chlorine atom 1-C 4Alkyl, more preferably methyl fluoride, difluoromethyl, trifluoromethyl, 2-fluoro ethyl, 2,2-two fluoro ethyls or 2,2,2-trifluoroethyl, particularly preferably trifluoromethyl.
At above-mentioned R 4And R 5" C in the definition 1-C 6Alkoxyl group " can be the abovementioned alkyl that has connected Sauerstoffatom; such as methoxyl group; oxyethyl group; propoxy-; isopropoxy; butoxy, isobutoxy, sec-butoxy, tert.-butoxy, pentyloxy, isopentyloxy, 2-methyl butoxy, neopentyl oxygen, 1-ethyl propoxy-, hexyloxy, 4-methyl pentyloxy, 3-methyl pentyloxy, 2-methyl pentyloxy, 1-methyl pentyloxy, 3,3-dimethyl butoxy, 2,2-dimethyl butoxy, 1,1-dimethyl butoxy, 1,2-dimethyl butoxy, 1,3-dimethyl butoxy, 2,3-dimethyl butoxy or 2-ethyl butoxy, preferably C 1-C 4Alkoxyl group, more preferably methoxy or ethoxy, particularly preferably methoxyl group.
At above-mentioned R 4And R 5" (C in the definition 1-C 6Alkoxyl group) carbonyl " can be for example with above-mentioned R 3Middle definition identical, preferably (C 1-C 4Alkoxyl group) carbonyl, more preferably methoxycarbonyl or ethoxycarbonyl, particularly preferably ethoxycarbonyl.
At above-mentioned R 4And R 5" (C in the definition 1-C 6Alkyl) formamyl " can be for example by above-mentioned C 1-C 6The formamyl that alkyl replaces; such as methylamino formyl radical, ethylamino formyl radical, propyl group formamyl, isopropylamino formyl radical, butyl formamyl, isobutylamino formyl radical, sec-butyl formamyl, tertiary butyl formamyl, amyl group formamyl or hexyl formamyl, preferably C 1-C 4Alkyl-carbamoyl, more preferably methylamino formyl radical or ethylamino formyl radical, particularly preferably methylamino formyl radical.
At above-mentioned R 4And R 5" two (C in the definition 1-C 6Alkyl) formamyl " can be for example by 2 identical or different above-mentioned C 1-C 6The formamyl that alkyl replaces, such as N, N-formyl-dimethylamino, N-ethyl-N-methylamino formyl radical, N; N-diethylamino formyl radical, N; N-dipropyl formamyl, N, N-diisopropylaminoethyl formyl radical, N, N-dibutylamino formyl radical, N; N-diisobutyl formamyl, N; N-di-sec-butyl formamyl, N, N-di-t-butyl formamyl, N, N-diamyl formamyl or N; N-dihexyl formamyl, preferably two (C 1-C 4Alkyl) formamyl, more preferably N, N-formyl-dimethylamino, N-ethyl-N-methylamino formyl radical or N, N-diethylamino formyl radical, N particularly preferably, N-formyl-dimethylamino.
General formula of the present invention (I) compound can change into acceptable salt on their corresponding pharmacology with acid treatment according to traditional method.For example, compound (I) (for example can be ethers, ester class or alcohols at solvent, preferred ethers or alcohols) in solution can at room temperature process 1-30 minute with corresponding acid, then filter to collect the crystallization of separating out or under reduced pressure steam solvent and just can obtain this salt.Example as this salt can be enumerated carbonate; Inorganic acid salt such as hydrofluoride, hydrochloride, hydrobromate, hydriodate, nitrate, perchlorate, vitriol or phosphoric acid salt etc.; Sulfonate such as mesylate, fluoroform sulphonate, esilate, benzene sulfonate or tosilate etc.; Carboxylate salt such as acetate, propionic salt, butyrates, fumarate, succinate, Citrate trianion, tartrate, oxalate, maleate or benzoate etc.; Or amino acid salts such as glutaminate or aspartate.
R 3In contain carboxyl etc. general formula of the present invention (I) compound can according to the traditional method alkaline purification, change into acceptable salt on their corresponding pharmacology.For example, compound (I) (for example can be ethers, ester class or alcohols at solvent, preferred ethers or alcohols) in solution can at room temperature process 1-30 minute with corresponding alkali, then filter to collect the crystallization of separating out or under reduced pressure steam solvent and just can obtain this salt.Example as this salt for example can be enumerated, an alkali metal salt such as sodium salt, sylvite or lithium salts etc.; Alkaline earth salt such as calcium salt or magnesium salts etc.; Metal-salt such as aluminium salt, molysite, zinc salt, mantoquita, nickel salt, cobalt salt etc.; Organic amine salt such as ammonium salt, uncle's octyl group amine salt, dibenzyl amine salt, alkylbenzyldimethylasaltsum saltsum, glucosamine salt, phenylglycocoll alkyl ester salt, ethylenediamine salt, N-METHYL-ALPHA-L-GLUCOSAMINE salt, guanidinesalt, diethyl amine salt, triethylamine salt, dicyclohexyl amine salt, N, N '-dibenzyl ethylenediamine salt, chloroprocaine salt, tetramethyl ammonium salt or three (methylol) aminomethane salt etc., preferred as alkali salt (especially sodium salt or sylvite).
Acceptable salt on general formula of the present invention (I) compound or its pharmacology, when in its molecule unsymmetrical carbon being arranged, there are (R) configuration or (S) steric isomer of configuration, any being included among the present invention in the compound of these isomer or its any ratio.These steric isomer compounds (I) for example can be synthetic with the starting compound of optical resolution, perhaps adopts common optical resolution technology or separation method that the racemic modification of formula (I) compound that synthesized is carried out optics and take apart.
When acceptable salt recrystallization on general formula of the present invention (I) compound or its pharmacology or when in atmosphere, placing, can absorb moisture and form hydrate.The present invention also comprises these hydrates.
In general formula of the present invention (I) compound, preferred compound for example can be enumerated:
(1) R wherein 1Hydrogen atom, fluorine atom, chlorine atom, bromine atoms, C 1-C 4The compound of alkyl or hydroxyl;
(2) R wherein 1It is the compound of hydrogen atom, fluorine atom, chlorine atom, methyl, ethyl or hydroxyl;
(3) R wherein 1It is the compound of hydrogen atom, fluorine atom, methyl or hydroxyl;
(4) R wherein 1It is the compound of hydrogen atom or hydroxyl;
(5) R wherein 2Hydrogen atom, fluorine atom, chlorine atom, bromine atoms or C 1-C 4The compound of alkyl;
(6) R wherein 2It is the compound of hydrogen atom, fluorine atom, chlorine atom, methyl or ethyl;
(7) R wherein 2It is the compound of hydrogen atom, fluorine atom or methyl;
(8) R wherein 2It is the compound of hydrogen atom or fluorine atom;
(9) R wherein 2It is the compound of hydrogen atom;
(10) such as undefined compound, wherein R 3Hydrogen atom, C 1-C 4Alkyl; Hydroxyl C 1-C 4Alkyl; Carboxyl C 1-C 4Alkyl or (C 1-C 4Alkoxyl group) carbonyl (C 1-C 4) alkyl; Group shown in the general formula (II):
Figure A0081780000191
R in the formula 7Represent C 1-C 4Alkyl, m and n are identical or different, represent the integer of 1-4; Benzyl, menaphthyl, diphenyl methyl or styroyl; C 1-C 4Alkanoyl; Hydroxyacetyl, 3-hydroxyl propionyl or 4-maloyl group; Methylsulfonyl, ethylsulfonyl, the third alkylsulfonyl, fourth alkylsulfonyl, penta alkylsulfonyl or own alkylsulfonyl; Or by (C 1-C 4Alkoxyl group) C of carbonyl or carboxyl substituted 1-C 4Alkyl sulphonyl.
(11) such as undefined compound, wherein R 3It is hydrogen atom; C 1-C 4Alkyl; 2-hydroxyethyl, carboxymethyl, methoxycarbonyl methyl, ethoxycarbonylmethyl group, the third oxygen carbonyl methyl or butoxy carbonyl methyl; Group shown in the general formula (II): R in the formula 7Represent methylidene or ethyl, m and n are identical or different, represent 1 or 2 integer; Benzyl or styroyl; Formyl radical or ethanoyl; Hydroxyacetyl; Methylsulfonyl, ethylsulfonyl or fourth alkylsulfonyl; Or by (C 1-C 4Alkoxyl group) methylsulfonyl of carbonyl or carboxyl substituted or ethylsulfonyl.
(12) such as undefined compound, wherein R 3Hydrogen atom, methyl, ethyl, sec.-propyl, 2-hydroxyethyl, carboxymethyl, methoxycarbonyl methyl, ethoxycarbonylmethyl group, the third oxygen carbonyl methyl, butoxy carbonyl methyl, ethanoyl, hydroxyacetyl, methylsulfonyl, ethylsulfonyl, fourth alkylsulfonyl, methoxycarbonyl methylsulfonyl, ethoxycarbonyl methylsulfonyl, carboxyl methylsulfonyl, 2-methoxycarbonyl ethylsulfonyl, 2-ethoxycarbonyl ethylsulfonyl or 2-carboxyl ethylsulfonyl.
(13) such as undefined compound, wherein R 3Sec.-propyl, 2-hydroxyethyl, carboxymethyl, methoxycarbonyl methyl, ethoxycarbonylmethyl group, ethylsulfonyl, methoxycarbonyl methylsulfonyl, ethoxycarbonyl methylsulfonyl, carboxyl methylsulfonyl, 2-methoxycarbonyl ethylsulfonyl, 2-ethoxycarbonyl ethylsulfonyl or 2-carboxyl ethylsulfonyl.
(14) such as undefined compound, wherein R 3Sec.-propyl, carboxymethyl, ethoxycarbonylmethyl group, ethoxycarbonyl methylsulfonyl or carboxyl methylsulfonyl.
(15) R wherein 3It is the compound of ethoxycarbonyl methylsulfonyl or carboxyl methylsulfonyl.
(16) such as undefined compound, wherein, R 4And R 5Identical or different, each represents hydrogen atom, fluorine atom, chlorine atom, bromine atoms, C 1-C 4Alkyl, methyl fluoride, difluoromethyl, trifluoromethyl, 2-fluoro ethyl, 2,2-two fluoro ethyls, 2,2,2-trifluoroethyl, C 1-C 4Alkoxyl group, carboxyl, methoxycarbonyl, ethoxycarbonyl, formamyl, methylamino formyl radical or N, the N-formyl-dimethylamino.
(17) such as undefined compound, wherein, R 4Hydrogen atom, fluorine atom, chlorine atom or trifluoromethyl,
R 5Hydrogen atom, fluorine atom, chlorine atom, bromine atoms, C 1-C 4Alkyl, methyl fluoride, difluoromethyl, trifluoromethyl, 2-fluoro ethyl, 2,2-two fluoro ethyls, 2,2,2-trifluoroethyl, C 1-C 4Alkoxyl group, carboxyl, methoxycarbonyl, ethoxycarbonyl, formamyl, methylamino formyl radical or N, the N-formyl-dimethylamino.
(18) such as undefined compound, wherein, R 4Hydrogen atom, fluorine atom or chlorine atom,
R 5Hydrogen atom, fluorine atom, chlorine atom, bromine atoms, methyl, ethyl, trifluoromethyl, methoxyl group, oxyethyl group or formamyl.
(19) such as undefined compound, wherein, R 4Hydrogen atom,
R 5Hydrogen atom, fluorine atom, chlorine atom, methyl, trifluoromethyl or formamyl.
(20) such as undefined compound, wherein, R 4Hydrogen atom,
R 5Hydrogen atom, chlorine atom, methyl or formamyl.
(21) R 6It is the compound of 1-acetimidoyl piperidin-4-yl.
R 1Preferred sequence be (1)-(4), R 2Preferred sequence be (5)-(9), R 3Preferred sequence be (10)-(15), R 4And R 5Preferred sequence be (16)-(20).
In addition, can enumerate the arbitrary combination of 2-5 the substituting group definition of from (1)-(4), (5)-(9), (10)-(15), (16)-(20) and (21), selecting as the example of above-mentioned general formula (I) compound, in these combinations preferably combination for example can enumerate:
(22) such as undefined compound, wherein:
R 1Hydrogen atom, fluorine atom, chlorine atom, bromine atoms, C 1-C 4Alkyl or hydroxyl;
R 2Hydrogen atom, fluorine atom, chlorine atom, bromine atoms or C 1-C 4Alkyl;
R 3Hydrogen atom, C 1-C 4Alkyl; Hydroxyl C 1-C 4Alkyl; Carboxyl C 1-C 4Alkyl or (C 1-C 4Alkoxyl group) carbonyl (C 1-C 4) alkyl; Group shown in the general formula (II): R in the formula 7Represent C 1-C 4Alkyl, m and n are identical or different, represent the integer of 1-4; Benzyl, menaphthyl, diphenyl methyl or styroyl; C 1-C 4Alkanoyl; Hydroxyacetyl, 3-hydroxyl propionyl or 4-maloyl group; Methylsulfonyl, ethylsulfonyl, the third alkylsulfonyl, fourth alkylsulfonyl, penta alkylsulfonyl or own alkylsulfonyl; Or by (C 1-C 4Alkoxyl group) C of carbonyl or carboxyl substituted 1-C 4Alkyl sulphonyl;
R 4And R 5Identical or different, each represents hydrogen atom, fluorine atom, chlorine atom, bromine atoms, C 1-C 4Alkyl, methyl fluoride, difluoromethyl, trifluoromethyl, 2-fluoro ethyl, 2,2-two fluoro ethyls, 2,2,2-trifluoroethyl, C 1-C 4Alkoxyl group, carboxyl, methoxycarbonyl, ethoxycarbonyl, formamyl, methylamino formyl radical or N, the N-formyl-dimethylamino.
(23) such as undefined compound, wherein:
R 1Hydrogen atom, fluorine atom, chlorine atom, methyl, ethyl or hydroxyl;
R 2Hydrogen atom, fluorine atom, chlorine atom, methyl or ethyl;
R 3It is hydrogen atom; C 1-C 4Alkyl; 2-hydroxyethyl, carboxymethyl, methoxycarbonyl methyl, ethoxycarbonylmethyl group, the third oxygen carbonyl methyl or butoxy carbonyl methyl; Group shown in the general formula (II):
Figure A0081780000212
R in the formula 7Represent methylidene or ethyl, m and n are identical or different, represent 1 or 2 integer; Benzyl or styroyl; Formyl radical or ethanoyl; Hydroxyacetyl; Methylsulfonyl, ethylsulfonyl or fourth alkylsulfonyl; Or by (C 1-C 4Alkoxyl group) methylsulfonyl of carbonyl or carboxyl substituted or ethylsulfonyl;
R 4Hydrogen atom, fluorine atom, chlorine atom or trifluoromethyl,
R 5Hydrogen atom, fluorine atom, chlorine atom, bromine atoms, C 1-C 4Alkyl, methyl fluoride, difluoromethyl, trifluoromethyl, 2-fluoro ethyl, 2,2-two fluoro ethyls, 2,2,2-trifluoroethyl, C 1-C 4Alkoxyl group, carboxyl, methoxycarbonyl, ethoxycarbonyl, formamyl, methylamino formyl radical or N, the N-formyl-dimethylamino;
R 6It is 1-acetimidoyl piperidin-4-yl.
(24) such as undefined compound, wherein:
R 1Hydrogen atom, fluorine atom, methyl or hydroxyl;
R 2Hydrogen atom, fluorine atom or methyl;
R 3Hydrogen atom, methyl, ethyl, sec.-propyl, 2-hydroxyethyl, carboxymethyl, methoxycarbonyl methyl, ethoxycarbonylmethyl group, the third oxygen carbonyl methyl, butoxy carbonyl methyl, ethanoyl, hydroxyacetyl, methylsulfonyl, ethylsulfonyl, fourth alkylsulfonyl, methoxycarbonyl methylsulfonyl, ethoxycarbonyl methylsulfonyl, carboxyl methylsulfonyl, 2-methoxycarbonyl ethylsulfonyl, 2-ethoxycarbonyl ethylsulfonyl or 2-carboxyl ethylsulfonyl;
R 4Hydrogen atom, fluorine atom or chlorine atom,
R 5Hydrogen atom, fluorine atom, chlorine atom, bromine atoms, methyl, ethyl, trifluoromethyl, methoxyl group, oxyethyl group or formamyl;
R 6It is 1-acetimidoyl piperidin-4-yl.
(25) such as undefined compound, wherein:
R 1Hydrogen atom or hydroxyl;
R 2Hydrogen atom or fluorine atom;
R 3Sec.-propyl, 2-hydroxyethyl, carboxymethyl, methoxycarbonyl methyl, ethoxycarbonylmethyl group, ethylsulfonyl, methoxycarbonyl methylsulfonyl, ethoxycarbonyl methylsulfonyl, carboxyl methylsulfonyl, 2-methoxycarbonyl ethylsulfonyl, 2-ethoxycarbonyl ethylsulfonyl or 2-carboxyl ethylsulfonyl;
R 4Hydrogen atom,
R 5Hydrogen atom, fluorine atom, chlorine atom, methyl, trifluoromethyl or formamyl;
R 6It is 1-acetimidoyl piperidin-4-yl.
(26) such as undefined compound, wherein:
R 1Hydrogen atom or hydroxyl;
R 2Hydrogen atom or fluorine atom;
R 3Sec.-propyl, carboxymethyl, ethoxycarbonylmethyl group, ethoxycarbonyl methylsulfonyl or carboxyl methylsulfonyl;
R 4Hydrogen atom,
R 5Hydrogen atom, chlorine atom, methyl or formamyl;
R 6It is 1-acetimidoyl piperidin-4-yl.
(27) such as undefined compound, wherein:
R 1Hydrogen atom or hydroxyl;
R 2Hydrogen atom or fluorine atom;
R 3Ethoxycarbonyl methylsulfonyl or carboxyl methylsulfonyl;
R 4Hydrogen atom,
R 5Hydrogen atom, chlorine atom, methyl or formamyl;
R 6It is 1-acetimidoyl piperidin-4-yl.
The preferred sequence of above-mentioned these compounds is (22)-(27).
Example as representational compound of the present invention can be enumerated the compound of putting down in writing in the following table, but compound of the present invention has more than and is limited to these.
The implication of used abbreviation is as follows in the table:
Ac: ethanoyl
AI: acetimidoyl
1-AI-Pip (4): 1-acetimidoyl piperidin-4-yl
1-AI-pyrd (3): 1-acetimidoyl piperidines-3-base
Bn: benzyl
Bu: butyl
IBu: isobutyl-
SBu: sec-butyl
TBu: the tertiary butyl
Byr: butyryl radicals
Et: ethyl
Hx: hexyl
Me: methyl
Np (1): 1-naphthyl
Np (2): 2-naphthyl
Ph: phenyl
Pn: amyl group
Pr: propyl group
IPr: sec.-propyl
Prn: propionyl
Va: pentanoyl
Table 1 Cpd  R 1  R 2  R 3       R 4       R 5      R 6 No 1    H    H    H         H         H        1-AI-Pyrd(3) 2    H    H    Me        H         H        1-AI-Pyrd(3) 3    H    H    Et        H         H        1-AI-Pyrd(3) 4    H    H    iPr       H         H        1-AI-Pyrd(3) 5    H    H    iPr       3-Cl      H        1-AI-Pyrd(3) 6    H    H    iPr       3-Me      H        1-AI-Pyrd(3) 7     H     H     iPr         3-CONH 2    H        1-AI-Pyrd(3) 8     H     H     iPr         3-F         5-F      1-AI-Pyrd(3) 9     H     H     iPr         3-Cl        5-Cl     1-AI-Pyrd(3) 10    H     H     iPr         3-Me        5-Me     1-AI-Pyrd(3) 11    H     H     iPr         3-Cl        5-CONH 2 1-AI-Pyrd(3) 12    H     H     iPr         2-Me        5-CONH 2 1-AI-Pyrd(3) 13    H     H     iPr         3-Me        5-CONH 2 1-AI-Pyrd(3) 14    H     H     iPr         3-CONH 2    5-CONH 2 1-AI-Pyrd(3) 15    6-OH  H     iPr         H           H        1-AI-Pyrd(3) 16    6-OH  H     iPr         3-Cl        H        1-AI-Pyrd(3) 17    6-OH  H     iPr         3-Me        H        1-AI-Pyrd(3) 18    6-OH  H     iPr         3-CONH 2    H        1-AI-Pyrd(3) 19    H     H     Bu          H           H        1-AI-Pyrd(3) 20    H     H     Pn          H           H        1-AI-Pyrd(3) 21    H     H     Hx          H           H        1-AI-Pyrd(3) 22    H     H     CH 2OH      H           H        1-AI-Pyrd(3) 23    H     H     (CH 2) 2OH  H           H        1-AI-Pyrd(3) 24    6-OH  H     (CH 2) 2OH  H           H        1-AI-Pyrd(3) 25    H     H     (CH 2) 3OH  H           H        1-AI-Pyrd(3) 26    H     H     (CH 2) 4OH  H           H        1-AI-Pyrd(3) 27    H     H     (CH 2) 5OH  H           H        1-AI-Pyrd(3) 28    H     H     (CH 2) 6OH  H           H        1-AI-Pyrd(3) 29    H     H     CH 2COOH    H           H        1-AI-Pyrd(3) 30    H     H     CH 2COOH    3-Cl        H        1-AI-Pyrd(3) 31    H     H     CH 2COOH    3-Me        H        1-AI-Pyrd(3) 32    H     H     CH 2COOH    3-CONH 2    H        1-AI-Pyrd(3)  33   H     H     CH 2COOH    3-F         5-F      1-AI-Pyrd(3) 34    H     H     CH 2COOH    3-Cl        5-Cl     1-AI-Pyrd(3) 35    H     H     CH 2COOH    3-Me        5-Me     1-AI-Pyrd(3) 36    H     H    CH 2COOH       3-Cl       5-CONH 2     1-AI-Pyrd(3) 37    H     H    CH 2COOH       2-Me       5-CONH 2     1-AI-Pyrd(3) 38    H     H    CH 2COOH       3-Me       5-CONH 2     1-AI-Pyrd(3) 39    H     H    CH 2COOH       3-CONH 2   5-CONH 2     1-AI-Pyrd(3) 40    6-OH  H    CH 2COOH       H          H            1-AI-Pyrd(3) 41    6-OH  H    CH 2COOH       3-Cl       H            1-AI-Pyrd(3) 42    6-OH  H    CH 2COOH       3-Me       H            1-AI-Pyrd(3) 43    6-OH  H    CH 2COOH       3-CONH 2   H            1-AI-Pyrd(3) 44    H     H    (CH 2) 2COOH   H          H            1-AI-Pyrd(3) 45    H     H    (CH 2) 3COOH   H          H            1-AI-Pyrd(3) 46    H     H    (CH 2) 4COOH   H          H            1-AI-Pyrd(3) 47    H     H    (CH 2) 5COOH   H          H            1-AI-Pyrd(3) 48    H     H    (CH 2) 6COOH   H          H            1-AI-Pyrd(3) 49    H     H    CH 2COOMe      H          H            1-AI-Pyrd(3) 50    H     H    CH 2COOEt      H          H            1-AI-Pyrd(3) 5 1   H     H    CH 2COOEt      3-Cl       H            1-AI-Pyrd(3) 52    H     H    CH 2COOEt      3-Me       H            1-AI-Pyrd(3) 53    H     H    CH 2COOEt      3-CONH 2   H            1-AI-Pyrd(3) 54    H     H    CH 2COOEt      3-F        5-F          1-AI-Pyrd) 55    H     H    CH 2COOEt      3-Cl       5-Cl         1-AI-Pyrd(3) 56    H     H    CH 2COOEt      3-Me       5-Me         1-AI-Pyrd(3) 57    H     H    CH 2COOEt      3-Cl       5-CONH 2     1-AI-Pyrd(3) 58    H     H    CH 2COOEt      2-Me       5-CONH 2     1-AI-Pyrd(3) 59    H     H    CH 2COOEt      3-Me       5-CONH 2     1-AI-Pyrd(3) 60    H     H    CH 2COOEt      3-CONH 2   5-CONH 2     1-AI-Pyrd(3) 61    6-OH  H    CH 2COOEt      H          H            1-AI-Pyrd(3) 62    6-OH  H    CH 2COOEt      3-Cl       H            1-AI-Pyrd(3) 63    6-OH  H    CH 2COOEt      3-Me       H            1-AI-Pyrd(3) 64    6-OH  H    CH 2COOEt      3-CONH 2   H            1-AI-Pyrd(3) 65    H    H    CH 2COOPr       H       H    1-AI-Pyrd(3) 66    H    H    CH 2COOBu       H       H    1-AI-Pyrd(3) 67    H    H    CH 2COOPn       H       H    1-AI-Pyrd(3) 68    H    H    CH 2COOHx       H       H    1-AI-Pyrd(3) 69    H    H    (CH 2) 2COOEt   H       H    1-AI-Pyrd(3) 70    H    H    (CH 2) 3COOMe   H       H    1-AI-Pyrd(3) 71    H    H    (CH 2) 4COOPr   H       H    1-AI-Pyrd(3) 72    H    H    (CH 2) 5COOBu   H       H    1-AI-Pyrd(3) 73    H    H    (CH 2) 6COOHx   H       H    1-AI-Pyrd(3) 74    H    H     Bn             H       H    1-AI-Pyrd(3) 75    H    H    (CH 2) 2Ph      H       H    1-AI-Pyrd(3) 76    H    H    (CH 2) 3Ph      H       H    1-AI-Pyrd(3) 77    H    H    (CH 2) 4Ph      H       H    1-AI-Pyrd(3) 78    H    H    CHO             H       H    1-AI-Pyrd(3) 79    H    H    Ac              H       H    1-AI-Pyrd(3) 80    H    H    Prn             H       H    1-AI-Pyrd(3) 81    H    H    Va              H       H    1-AI-Pyrd(3) 82    H    H    SO 2Me          H       H    1-AI-Pyrd(3) 83    H    H    SO 2Et          H       H    1-AI-Pyrd(3) 84    6-OH H    SO 2Et          H       H    1-AI-Pyrd(3) 85    H    H    SO 2Pr          H       H    1-AI-Pyrd(3) 86    H    H    SO 2Bu          H       H    1-AI-Pyrd(3) 87    H    H    SO 2Pn          H       H    1-AI-Pyrd(3) 88    H    H    SO 2Hx          H       H    1-AI-Pyrd(3) 89    H    H    SO 2CH 2COOMe   H       H    1-AI-Pyrd(3) 90    H    H    SO 2CH 2COOEt   H       H    1-AI-Pyrd(3) 91    H    H    SO 2CH 2COOEt   3-F     H    1-AI-Pyrd(3) 92    H    H    SO 2CH 2COOEt   2-Cl    H    1-AI-Pyrd(3) 93    H    H    SO 2CH 2COOEt   3-Cl    H    1-AI-Pyrd(3) 94    H      H    SO 2CH 2COOEt    2-Me     H          1-AI-Pyrd(3) 95    H      H    SO 2CH 2COOEt    3-Me     H          1-AI-Pyrd(3) 96    H      H    SO 2CH 2COOEt    3-Et     H          1-AI-Pyrd(3) 97    H      H    SO 2CH 2COOEt    3-CF 3   H          1-AI-Pyrd(3) 98    H      H    SO 2CH 2COOEt    2-OEt    H          1-AI-Pyrd(3) 99    H      H    SO 2CH 2COOEt    3-OMe    H          1-AI-Pyrd(3) 100   H      H    SO 2CH 2COOEt    2-CONH 2 H          1-AI-Pyrd(3) 101   H      H    SO 2CH 2COOEt    3-CONH 2 H          1-AI-Pyrd(3) 102   H      H    SO 2CH 2COOEt    3-F      5-F        1-AI-Pyrd(3) 103   H      H    SO 2CH 2COOEt    3-Cl     5-Cl       1-AI-Pyrd(3) 104   H      H    SO 2CH 2COOEt    3-Me     5-Me       1-AI-Pyrd(3) 105   H      H    SO 2CH 2COOEt    3-Cl     5-CONH 2   1-AI-Pyrd(3) 106   H      H    SO 2CH 2COOEt    2-Me     5-CONH 2   1-AI-Pyrd(3) 107   H      H    SO 2CH 2COOEt    3-Me     5-CONH 2   1-AI-Pyrd(3) 108   H      H    SO 2CH 2COOEt    3-CONH 2 5-CONH 2   1-AI-Pyrd(3) 109   H      F    SO 2CH 2COOEt    H        H          1-AI-Pyrd(3) 110   H      Cl   SO 2CH 2COOEt    H        H          1-AI-Pyrd(3) 111   H      Me   SO 2CH 2COOEt    H        H          1-AI-Pyrd(3) 112   H      Et   SO 2CH 2COOEt    H        H          1-AI-Pyrd(3) 113   2-F    H    SO 2CH 2COOEt    H        H          1-AI-Pyrd(3) 114   4-F    H    SO 2CH 2COOEt    H        H          1-AI-Pyrd(3) 115   5-F    H    SO 2CH 2COOEt    H        H          1-AI-Pyrd(3) 116   6-F    H    SO 2CH 2COOEt    H        H          1-AI-Pyrd(3) 117   2-Cl   H    SO 2CH 2COOEt    H        H          1-AI-Pyrd(3) 118   6-Cl   H    SO 2CH 2COOEt    H        H          1-AI-Pyrd(3) 119   4-Me   H    SO 2CH 2COOEt    H        H          1-AI-Pyrd(3) 120   6-Me   H    SO 2CH 2COOEt    H        H          1-AI-Pyrd(3) 121   5-Et   H    SO 2CH 2COOEt    H        H          1-AI-Pyrd(3) 122   6-Pr   H    SO 2CH 2COOEt    H        H          1-AI-Pyrd(3) 123  2-OH  H    SO 2CH 2COOEt        H         H       1-AI-Pyrd(3) 124  4-OH  H    SO 2CH 2COOEt        H         H       1-AI-Pyrd(3) 125  5-OH  H    SO 2CH 2COOEt        H         H       1-AI-Pyrd(3) 126  6-OH  H    SO 2CH 2COOEt        H         H       1-AI-Pyrd(3) 127  H     H    SO 2CH 2COOPr        H         H       1-AI-Pyrd(3) 128  H     H    SO 2CH 2COOBu        H         H       1-AI-Pyrd(3) 129  H     H    SO 2CH 2COOPn        H         H       1-AI-Pyrd(3) 130  H     H    SO 2CH 2COOHx        H         H       1-AI-Pyrd(3) 131  H     H    SO 2(CH 2) 2COOMe    H         H       1-AI-Pyrd(3) 132  H     H    SO 2(CH 2) 2COOEt    H         H       1-AI-Pyrd(3) 133  H     H    SO 2(CH 2) 2COOPr    H         H       1-AI-Pyrd(3) 134  H     H    SO 2(CH 2) 2COOBu    H         H       1-AI-Pyrd(3) 135  H     H    SO 2(CH 2) 2COOPn    H         H       1-AI-Pyrd(3) 136  H     H    SO 2(CH 2) 2COOOHx   H         H       1-AI-Pyrd(3) 137  H     H    SO 2CH 2COOH         H         H       1-AI-Pyrd(3) 138  H     H    SO 2CH 2OOH          3-F       H       1-AI-Pyrd(3) 139  H     H    SO 2CH 2COOH         2-Cl      H       1-AI-Pyrd(3) 140  H     H    SO 2CH 2COOH         3-Cl      H       1-AI-Pyrd(3) 141  H     H    SO 2CH 2COOH         2-Me      H       1-AI-Pyrd(3) 142  H     H    SO 2CH 2COOH         3-Me      H       1-AI-Pyrd(3) 143  H     H    SO 2CH 2COOH         3-Et      H       1-AI-Pyrd(3) 144  H     H    SO 2CH 2COOH         3-CF 3    H       1-AI-Pyrd(3) 145  H     H    SO 2CH 2COOH         2-OMe     H       1-AI-Pyrd(3) 146  H     H    SO 2CH 2COOH         3-OEt     H       1-AI-Pyrd(3) 147  H     H    SO 2CH 2COOH         2-CONH 2  H       1-AI-Pyrd(3) 148  H     H    SO 2CH 2COOH         3-CONH 2  H       1-AI-Pyrd(3) 149  H     H    SO 2CH 2COOH         3-F       5-F     1-AI-Pyrd(3) 150  H     H    SO 2CH 2COOH         3-Cl      5-Cl    1-AI-Pyrd(3) 151  H     H    SO 2CH 2COOH         3-Me      5-Me    1-AI-Pyrd(3) 152  H     H    SO 2CH 2COOH       3-Cl       5-CONH 2  1-AI-Pyrd(3) 153  H     H    SO 2CH 2COOH       2-Me       5-CONH 2  1-AI-Pyrd(3) 154  H     H    SO 2CH 2COOH       3-Me       5-CONH 2  1-AI-Pyrd(3) 155  H     H    SO 2CH 2COOH       3-CONH 2   5-CONH 2  1-AI-Pyrd(3) 156  H     F    SO 2CH 2COOH       H          H         1-AI-Pyrd(3) 157  H     Cl   SO 2CH 2COOH       H          H         1-AI-Pyrd(3) 158  H     Me   SO 2CH 2COOH       H          H         1-AI-Pyrd(3) 159  H     Et   SO 2CH 2COOH       H          H         1-AI-Pyrd(3) 160  2-F   H    SO 2CH 2COOH       H          H         1-AI-Pyrd(3) 161  4-F   H    SO 2CH 2COOH       H          H         1-AI-Pyrd(3) 162  5-F   H    SO 2CH 2COOH       H          H         1-AI-Pyrd(3) 163  6-F   H    SO 2CH 2COOH       H          H         1-AI-Pyrd(3) 164  2-Cl  H    SO 2CH 2COOH       H          H         1-AI-Pyrd(3) 165  6-Cl  H    SO 2CH 2COOH       H          H         1-AI-Pyrd(3) 166  4-Me  H    SO 2CH 2COOH       H          H         1-AI-Pyrd(3) 167  6-Me  H    SO 2CH 2COOH       H          H         1-AI-Pyrd(3) 168  5-Et  H    SO 2CH 2COOH       H          H         1-AI-Pyrd(3) 169  6-Pr  H    SO 2CH 2COOH       H          H         1-AI-Pyrd(3) 170  2-OH  H    SO 2CH 2COOH       H          H         1-AI-Pyrd(3) 171  4-OH  H    SO 2CH 2COOH       H          H         1-AI-Pyrd(3) 172  5-OH  H    SO 2CH 2COOH       H          H         1-AI-Pyrd(3) 173  6-OH  H    SO 2CH 2COOH       H          H         1-AI-Pyrd(3) 174  H     H    SO 2CH 2COOH       H          H         1-AI-Pyrd(3) 175  H     H    SO 2CH 2COOH       H          H         1-AI-Pyrd(3) 176  H     H    SO 2(CH 2) 2COOH   H          H         1-AI-Pyrd(3) 177  H     H    H                   H          H         1-AI-Pip(4) 178  H     H    H                   2-F        H         1-AI-Pip(4) 179  H     H    H                   3-F        H         1-AI-Pip(4) 180  H     H    H                   2-Cl       H         1-AI-Pip(4) 181  H    H    H    3-Cl      H    1-AI-Pip(4) 182  H    H    H    2-Br      H    1-AI-Pip(4) 183  H    H    H    3-Br      H    1-AI-Pip(4) 184  H    H    H    2-I       H    1-AI-Pip(4) 185  H    H    H    3-I       H    1-AI-Pip(4) 186  H    H    H    2-Me      H    1-AI-Pip(4) 187  H    H    H    3-Me      H    1-AI-Pip(4) 188  H    H    H    2-Et      H    1-AI-Pip(4) 189  H    H    H    3-Et      H    1-AI-Pip(4) 190  H    H    H    2-Pr      H    1-AI-Pip(4) 191  H    H    H    3-Pr      H    1-AI-Pip(4) 192  H    H    H    2-Bu      H    1-AI-Pip(4) 193  H    H    H    3-Bu      H    1-AI-Pip(4) 194  H    H    H    2-Pn      H    1-AI-Pip(4) 195  H    H    H    3-Pn      H    1-AI-Pip(4) 196  H    H    H    2-Hx      H    1-AI-Pip(4) 197  H    H    H    3-Hx      H    1-AI-Pip(4) 198  H    H    H    2-CF 3    H    1-AI-Pip(4) 199  H    H    H    3-CF 3    H    1-AI-Pip(4) 200  H    H    H    2-OMe     H    1-AI-Pip(4) 201  H    H    H    3-OMe     H    1-AI-Pip(4) 202  H    H    H    2-OEt     H    1-AI-Pip(4) 203  H    H    H    3-OEt     H    1-AI-Pip(4) 204  H    H    H    2-COOH    H    1-AI-Pip(4) 205  H    H    H    3-COOH    H    1-AI-Pip(4) 206  H    H    H    2-COOMe   H    1-AI-Pip(4) 207  H    H    H    3-COOMe   H    1-AI-Pip(4) 208  H    H    H    2-COOEt   H    1-AI-Pip(4) 209  H    H    H    3-COOEt   H    1-AI-Pip(4) 21O  H    H    H    2-COOPr      H          1-AI-Pip(4) 211  H    H    H    3-COOPr      H          1-AI-Pip(4) 212  H    H    H    2-COOBu      H          1-AI-Pip(4) 213  H    H    H    3-COOBu      H          1-AI-Pip(4) 214  H    H    H    2-COOPn      H          1-AI-Pip(4) 215  H    H    H    3-COOPn      H          1-AI-Pip(4) 216  H    H    H    2-COOHx      H          1-AI-Pip(4) 217  H    H    H    3-COOHx      H          1-AI-Pip(4) 218  H    H    H    2-CONH 2     H          1-AI-Pip(4) 219  H    H    H    3-CONH 2     H          1-AI-Pip(4) 220  H    H    H    2-CONHMe     H          1-AI-Pip(4) 221  H    H    H    3-CONHMe     H          1-AI-Pip(4) 222  H    H    H    2-CONHEt     H          1-AI-Pip(4) 223  H    H    H    3-CONHEt     H          1-AI-Pip(4) 224  H    H    H    2-CON(Me) 2  H          1-AI-Pip(4) 225  H    H    H    3-CON(Me) 2  H          1-AI-Pip(4) 226  H    H    H    2-CON(Me)Et  H          1-AI-Pip(4) 227  H    H    H    3-CON(Me)Et  H          1-AI-Pip(4) 228  H    H    H    2-CON(Et) 2  H          1-AI-Pip(4) 229  H    H    H    3-CON(Et) 2  H          1-AI-Pip(4) 230  H    H    H    3-F          5-F        1-AI-Pip(4) 231  H    H    H    3-Cl         3-Cl       1-AI-Pip(4) 232  H    H    H    3-Me         5-Me       1-AI-Pip(4) 233  H    H    H    3-Cl         5-CONH 2   1-AI-Pip(4) 234  H    H    H    2-Me         5-CONH 2   1-AI-Pip(4) 235  H    H    H    3-Me         5-CONH 2   1-AI-Pip(4) 236  H    H    H    3-CONH 2     3-CONH 2   1-AI-Pip(4) 237  H    H    Me   H            H          1-AI-Pip(4) 238  H    H    Me   2-F          H          1-AI-Pip(4) 239  H    H  Me    3-F      H    1-AI-Pip(4) 240  H    H  Me    2-Cl     H    1-AI-Pip(4) 241  H    H  Me    3-Cl     H    1-AI-Pip(4) 242  H    H  Me    2-Br     H    1-AI-Pip(4) 243  H    H  Me    3-Br     H    1-AI-Pip(4) 244  H    H  Me    2-I      H    1-AI-Pip(4) 245  H    H  Me    3-I      H    1-AI-Pip(4) 246  H    H  Me    2-Me     H    1-AI-Pip(4) 247  H    H  Me    3-Me     H    1-AI-Pip(4) 248  H    H  Me    2-Et     H    1-AI-Pip(4) 249  H    H  Me    3-Et     H    1-AI-Pip(4) 250  H    H  Me    2-Pr     H    1-AI-Pip(4) 251  H    H  Me    3-Pr     H    1-AI-Pip(4) 252  H    H  Me    2-Bu     H    1-AI-Pip(4) 253  H    H  Me    3-Bu     H    1-AI-Pip(4) 254  H    H  Me    2-Pn     H    1-AI-Pip(4) 255  H    H  Me    3-Pn     H    1-AI-Pip(4) 256  H    H  Me    2-Hx     H    1-AI-Pip(4) 257  H    H  Me    3-Hx     H    1-AI-Pip(4) 258  H    H  Me    2-CF 3   H    1-AI-Pip(4) 259  H    H  Me    3-CF 3   H    1-AI-Pip(4) 260  H    H  Me    2-OMe    H    1-AI-Pip(4) 261  H    H  Me    3-OMe    H    1-AI-Pip(4) 262  H    H  Me    2-OEt    H    1-AI-Pip(4) 263  H    H  Me    3-OEt    H    1-AI-Pip(4) 264  H    H  Me    2-COOH   H    1-AI-Pip(4) 265  H    H  Me    3-COOH   H    1-AI-Pip(4) 266  H    H  Me    2-COOMe  H    1-AI-Pip(4) 267  H    H  Me    3-COOMe  H    1-AI-Pip(4) 268  H    H   Me    2-COOEt       H          1-AI-Pip(4) 269  H    H   Me    3-COOEt       H          1-AI-Pip(4) 270  H    H   Me    2-COOPr       H          1-AI-Pip(4) 271  H    H   Me    3-COOPr       H          1-AI-Pip(4) 272  H    H   Me    2-COOBu       H          1-AI-Pip(4) 273  H    H   Me    3-COOBu       H          1-AI-Pip(4) 274  H    H   Me    2-COOPn       H          1-AI-Pip(4) 275  H    H   Me    3-COOPn       H          1-AI-Pip(4) 276  H    H   Me    2-COOHx       H          1-AI-Pip(4) 277  H    H   Me    3-COOHx       H          1-AI-Pip(4) 278  H    H   Me    2-CONH 2      H          1-AI-Pip(4)       279  H    H   Me    3-CONH 2      H          1-AI-Pip(4) 280  H    H   Me    2-CONHMe      H          1-AI-Pip(4) 281  H    H   Me    3-CONHMe      H          1-AI-Pip(4) 282  H    H   Me    2-CONHEt      H          1-AI-Pip(4) 283  H    H   Me    3-CONHEt      H          1-AI-Pip(4) 284  H    H   Me    2-CON(Me) 2   H          1-AI-Pip(4) 285  H    H   Me    3-CON(Me) 2   H          1-AI-Pip(4) 286  H    H   Me    2-CON(Me)Et   H          1-AI-Pip(4) 287  H    H   Me    3-CON(Me)Et   H          1-AI-Pip(4) 288  H    H   Me    2-CON(Et) 2   H          1-AI-Pip(4) 289  H    H   Me    3-CON(Et) 2   H          1-AI-Pip(4) 290  H    H   Me    3-F           5-F        1-AI-Pip(4) 291  H    H   Me    3-Cl          5-Cl       1-AI-Pip(4) 292  H    H   Me    3-Me          5-Me       1-AI-Pip(4) 293  H    H   Me    3-Cl          5-CONH 2   1-AI-Pip(4) 294  H    H   Me    2-Me          5-CONH 2   1-AI-Pip(4) 295  H    H   Me    3-Me          5-CONH 2   1-AI-Pip(4) 296  H    H   Me    3-CONH 2      5-CONH 2   1-AI-Pip(4) 297  H    H    Et    H         H    1-AI-Pip(4) 298  H    H    Et    2-F       H    1-AI-Pip(4) 299  H    H    Et    3-F       H    1-AI-Pip(4) 300  H    H    Et    2-Cl      H    1-AI-Pip(4) 301  H    H    Et    3-Cl      H    1-AI-Pip(4) 302  H    H    Et    2-Br      H    1-AI-Pip(4) 303  H    H    Et    3-Br      H    1-AI-Pip(4) 304  H    H    Et    2-I       H    1-AI-Pip(4) 305  H    H    Et    3-I       H    1-AI-Pip(4) 306  H    H    Et    2-Me      H    1-AI-Pip(4) 307  H    H    Et    3-Me      H    1-AI-Pip(4) 308  H    H    Et    2-Et      H    1-AI-Pip(4) 309  H    H    Et    3-Et      H    1-AI-Pip(4) 310  H    H    Et    2-Pr      H    1-AI-Pip(4) 311  H    H    Et    3-Pr      H    1-AI-Pip(4) 312  H    H    Et    2-Bu      H    1-AI-Pip(4) 313  H    H    Et    3-Bu      H    1-AI-Pip(4) 314  H    H    Et    2-Pn      H    1-AI-Pip(4) 315  H    H    Et    3-Pn      H    1-AI-Pip(4) 316  H    H    Et    2-Hx      H    1-AI-Pip(4) 317  H    H    Et    3-Hx      H    1-AI-Pip(4) 318  H    H    Et    2-CF 3    H    1-AI-Pip(4) 319  H    H    Et    3-CF 3    H    1-AI-Pip(4) 320  H    H    Et    2-OMe     H    1-AI-Pip(4) 321  H    H    Et    3-OMe     H    1-AI-Pip(4) 322  H    H    Et    2-OEt     H    1-AI-Pip(4) 323  H    H    Et    3-OEt     H    1-AI-Pip(4) 324  H    H    Et    2-COOH    H    1-AI-Pip(4) 325  H    H    Et    3-COOH    H    1-AI-Pip(4) 326  H    H    Et    2-COOMe       H         1-AI-Pip(4) 327  H    H    Et    3-COOMe       H         1-AI-Pip(4) 328  H    H    Et    2-COOEt       H         1-AI-Pip(4) 329  H    H    Et    3-COOEt       H         1-AI-Pip(4) 330  H    H    Et    2-COOPr       H         1-AI-Pip(4) 331  H    H    Et    3-COOPr       H         1-AI-Pip(4) 332  H    H    Et    2-COOBu       H         1-AI-Pip(4) 333  H    H    Et    3-COOBu       H         1-AI-Pip(4) 334  H    H    Et    2-COOPn       H         1-AI-Pip(4) 335  H    H    Et    3-COOPn       H         1-AI-Pip(4) 336  H    H    Et    2-COOHx       H         1-AI-Pip(4) 337  H    H    Et    3-COOHx       H         1-AI-Pip(4) 338  H    H    Et    2-COONH 2     H         1-AI-Pip(4) 339  H    H    Et    3-CONH 2      H         11-AI-Pip(4) 340  H    H    Et    2-CONHMe      H         1-AI-Pip(4) 341  H    H    Et    3-CONHMe      H         1-AI-Pip(4) 342  H    H    Et    2-CONHEt      H         1-AI-Pip(4) 343  H    H    Et    3-CONHEt      H         1-AI-Pip(4) 344  H    H    Et    2-CON(Me) 2   H         1-AI-Pip(4) 345  H    H    Et    3-CON(Me) 2   H         1-AI-Pip(4) 346  H    H    Et    2-CON(Me)Et   H         1-AI-Pip(4) 347  H    H    Et    3-CON(Me)Et   H         1-AI-Pip(4) 348  H    H    Et    2-CON(Et) 2   H         1-AI-Pip(4) 349  H    H    Et    3-CON(Et) 2   H         1-AI-Pip(4) 350  H    H    Et    3-F           5-F       1-AI-Pip(4) 351  H    H    Et    3-C1          5-Cl      1-AI-Pip(4) 352  H    H    Et    3-Me          5-Me      1-AI-Pip(4) 353  H    H    Et    3-Cl          5-CONH 2  1-AI-Pip(4) 354  H    H    Et    2-Me          5-CONH 2  1-AI-Pip(4) 355  H   H   Et     3-Me       5-CONH 2 1-AI-Pip(4) 356  H   H   Et     3-CONH 2   5-CONH 2 1-AI-Pip(4) 357  H   H   Pr     H          H        1-AI-Pip(4) 358  H   H   iPr    H          H        1-AI-Pip(4) 359  H   H   iPr    2-F        H        1-AI-Pip(4) 360  H   H   iPr    3-F        H        1-AI-Pip(4) 361  H   H   iPr    2-Cl       H        1-AI-Pip(4) 362  H   H   iPr    3-Cl       H        1-AI-Pip(4) 363  H   H   iPr    2-Br       H        1-AI-Pip(4) 364  H   H   iPr    3-Br       H        1-AI-Pip(4) 365  H   H   iPr    2-I        H        1-AI-Pip(4) 366  H   H   iPr    3-I        H        1-AI-Pip(4) 367  H   H   iPr    2-Me       H        1-AI-Pip(4) 368  H   H   iPr    3-Me       H        1-AI-Pip(4) 369  H   H   iPr    2-Et       H        1-AI-Pip(4) 370  H   H   iPr    3-Et       H        1-AI-Pip(4) 371  H   H   iPr    2-Pr       H        1-AI-Pip(4) 372  H   H   iPr    3-Pr       H        1-AI-Pip(4) 373  H   H   iPr    2-Bu       H        1-AI-Pip(4) 374  H   H   iPr    3-Bu       H        1-AI-Pip(4) 375  H   H   iPr    2-Pn       H        1-AI-Pip(4) 376  H   H   iPr    3-Pn       H        1-AI-Pip(4) 377  H   H   iPr    2-Hx       H        1-AI-Pip(4) 378  H   H   iPr    3-Hx       H        1-AI-Pip(4) 379  H   H   iPr    2-CF 3     H        1-AI-Pip(4) 380  H   H   iPr    3-CF 3     H        1-AI-Pip(4) 381  H   H   iPr    2-OMe      H        1-AI-Pip(4) 382  H   H   iPr    3-OMe      H        1-AI-Pip(4) 383  H   H   iPr    2-OEt      H        1-AI-Pip(4) 384   H   H   iPr    3-OEt         H        1-AI-Pip(4) 385   H   H   iPr    2-COOH        H        1-AI-Pip(4) 386   H   H   iPr    3-COOH        H        1-AI-Pip(4) 387   H   H   iPr    2-COOMe       H        1-AI-Pip(4) 388   H   H   iPr    3-COOMe       H        1-AI-Pip(4) 389   H   H   iPr    2-COOEt       H        1-AI-Pip(4) 390   H   H   iPr    3-COOEt       H        1-AI-Pip(4) 391   H   H   iPr    2-COOPr       H        1-AI-Pip(4) 392   H   H   iPr    3-COOPr       H        1-AI-Pip(4) 393   H   H   iPr    2-COOBu       H        1-AI-Pip(4) 394   H   H   iPr    3-COOBu       H        1-AI-Pip(4) 395   H   H   iPr    2-COOPn       H        1-AI-Pip(4) 396   H   H   iPr    3-COOPn       H        1-AI-Pip(4) 397   H   H   iPr    2-COOHx       H        1-AI-Pip(4) 398   H   H   iPr    3-COOHx       H        1-AI-Pip(4) 399   H   H   iPr    2-CONH 2      H        1-AI-Pip(4) 400   H   H   iPr    3-CONH 2      H        1-AI-Pip(4) 401   H   H   iPr    2-CONHMe      H        1-AI-Pip(4) 402   H   H   iPr    3-CONHMe      H        1-AI-Pip(4) 403   H   H   iPr    2-CONHEt      H        1-AI-Pip(4) 404   H   H   iPr    3-CONHEt      H        1-AI-Pip(4) 405   H   H   iPr    2-CON(Me) 2   H        1-AI-Pip(4) 406   H   H   iPr    3-CON(Me) 2   H        1-AI-Pip(4) 407   H   H   iPr    2-CON(Me)Et   H        1-AI-Pip(4) 408   H   H   iPr    3-CON(Me)Et   H        1-AI-Pip(4) 409   H   H   iPr    2-CON(Et) 2   H        1-AI-Pip(4) 410   H   H   iPr    3-CON(Et) 2   H        1-AI-Pip(4) 411   H   H   iPr    3-F           5-F      1-AI-Pip(4) 412   H   H   iPr    3-Cl          5-Cl     1-AI-Pip(4) 413  H      H   iPr    3-Me      5-Me     1-AI-Pip(4) 414  H      H   iPr    3-C1      5-ONH 2  1-AI-Pip(4) 415  H      H   iPr    2-Me      5-CONH 2 1-AI-Pip(4) 416  H      H   iPr    3-Me      5-CONH 2 1-AI-Pip(4) 417  H      H   iPr    3-CONH 2  5-CONH 2 1-AI-Pip(4) 418  6-OH   H   iPr    H         H        1-AI-Pip(4) 419  6-OH   H   iPr    2-F       H        1-AI-Pip(4) 420  6-OH   H   iPr    3-F       H        1-AI-Pip(4) 421  6-OH   H   iPr    2-Cl      H        1-AI-Pip(4) 422  6-OH   H   iPr    3-Cl      H        1-AI-Pip(4) 423  6-OH   H   iPr    2-Br      H        1-AI-Pip(4) 424  6-OH   H   iPr    3-Br      H        1-AI-Pip(4) 425  6-OH   H   iPr    2-I       H        1-AI-Pip(4) 426  6-OH   H   iPr    3-I       H        1-AI-Pip(4) 427  6-OH   H   iPr    2-Me      H        1-AI-Pip(4) 428  6-OH   H   iPr    3-Me      H        1-AI-Pip(4) 429  6-OH   H   iPr    2-Et      H        1-AI-Pip(4) 430  6-OH   H   iPr    3-Et      H        1-AI-Pip(4) 431  6-OH   H   iPr    2-Pr      H        1-AI-Pip(4) 432  6-OH   H   iPr    3-Pr      H        1-AI-Pip(4) 433  6-OH   H   iPr    2-Bu      H        1-AI-Pip(4) 434  6-OH   H   iPr    3-Bu      H        1-AI-Pip(4) 435  6-OH   H   iPr    2-Pn      H        1-AI-Pip(4) 436  6-OH   H   iPr    3-Pn      H        1-AI-Pip(4) 437  6-OH   H   iPr    2-Hx      H        1-AI-Pip(4) 438  6-OH   H   iPr    3-Hx      H        1-AI-Pip(4) 439  6-OH   H   iPr    2-CF 3    H        1-AI-Pip(4) 440  6-OH   H   iPr    3-CF 3    H        1-AI-Pip(4) 441  6-OH   H   iPr    2-OMe     H        1-AI-Pip(4) 442  6-OH   H   iPr    3-OMe         H    1-AI-Pip(4) 443  6-OH   H   iPr    2-OEt         H    1-AI-Pip(4) 444  6-OH   H   iPr    3-OEt         H    1-AI-Pip(4) 445  6-OH   H   iPr    2-COOH        H    1-AI-Pip(4) 446  6-OH   H   iPr    3-COOH        H    1-AI-Pip(4) 447  6-OH   H   iPr    2-COOMe       H    1-AI-Pip(4) 448  6-OH   H   iPr    3-COOMe       H    1-AI-Pip(4) 449  6-OH   H   iPr    2-COOEt       H    1-AI-Pip(4) 450  6-OH   H   iPr    3-COOEt       H    1-AI-Pip(4) 451  6-OH   H   iPr    2-COOPr       H    1-AI-Pip(4) 452  6-OH   H   iPr    3-COOPr       H    1-AI-Pip(4) 453  6-OH   H   iPr    2-COOBu       H    1-AI-Pip(4) 454  6-OH   H   iPr    3-COOBu       H    1-AI-Pip(4) 455  6-OH   H   iPr    2-COOPn       H    1-AI-Pip(4) 456  6-OH   H   iPr    3-COOPn       H    1-AI-Pip(4) 457  6-OH   H   iPr    2-COOHx       H    1-AI-Pip(4) 458  6-OH   H   iPr    3-COOHx       H    1-AI-Pip(4) 459  6-OH   H   iPr    2-CONH 2      H    1-AI-Pip(4) 460  6-OH   H   iPr    3-CONH 2      H    1-AI-Pip(4) 461  6-OH   H   iPr    2-CONHMe      H    1-AI-Pip(4) 462  6-OH   H   iPr    3-CONHMe      H    1-AI-Pip(4) 463  6-OH   H   iPr    2-CONHEt      H    1-AI-Pip(4) 464  6-OH   H   iPr    3-CONHEt      H    1-AI-Pip(4) 465  6-OH   H   iPr    2-CON(Me) 2   H    1-AI-Pip(4) 466  6-OH   H   iPr    3-CON(Me) 2   H    1-AI-Pip(4) 467  6-OH   H   iPr    2-CON(Me)Et   H    1-AI-Pip(4) 468  6-OH   H   iPr    3-CON(Me)Et   H    1-AI-Pip(4) 469  6-OH   H   iPr    2-CON(Et) 2   H    1-AI-Pip(4) 470  6-OH   H   iPr    3-CON(Et) 2   H    1-AI-Pip(4) 471  H   H   Bu            H       H    1-AI-Pip(4) 472  H   H   iBu           H       H    1-AI-Pip(4) 473  H   H   sBu           H       H    1-AI-Pip(4) 474  H   H   tBu           H       H    1-AI-Pip(4) 475  H   H   Pn            H       H    1-AI-Pip(4) 476  H   H   Hx            H       H    1-AI-Pip(4) 477  H   H   CH 2OH        H       H    1-AI-Pip(4) 478  H   H   (CH 2) 2OH    H       H    1-AI-Pip(4) 479  H   H   (CH 2) 2OH    2-F     H    1-AI-Pip(4) 480  H   H   (CH 2) 2OH    3-F     H    1-AI-Pip(4) 481  H   H   (CH 2) 2OH    2-Cl    H    1-AI-Pip(4) 482  H   H   (CH 2) 2OH    3-Cl    H    1-AI-Pip(4) 483  H   H   (CH 2) 2OH    2-Br    H    1-AI-Pip(4) 484  H   H   (CH 2) 2OH    3-Br    H    1-AI-Pip(4) 485  H   H   (CH 2) 2OH    2-I     H    1-AI-Pip(4) 486  H   H   (CH 2) 2OH    3-I     H    1-AI-Pip(4) 487  H   H   (CH 2) 2OH    2-Me    H    1-AI-Pip(4) 488  H   H   (CH 2) 2OH    3-Me    H    1-AI-Pip(4) 489  H   H   (CH 2) 2OH    2-Et    H    1-AI-Pip(4) 490  H   H   (CH 2) 2OH    3-Et    H    1-AI-Pip(4) 491  H   H   (CH 2) 2OH    2-Pr    H    1-AI-Pip(4) 492  H   H   (CH 2) 2OH    3-Pr    H    1-AI-Pip(4) 493  H   H   (CH 2) 2OH    2-Bu    H    1-AI-Pip(4) 494  H   H   (CH 2) 2OH    3-Bu    H    1-AI-Pip(4)  495  H   H   (CH 2) 2OH    2-Pn    H    1-AI-Pip(4) 496  H   H   (CH 2) 2OH    3-Pn    H    1-AI-Pip(4) 497  H   H   (CH 2) 2OH    2-Hx    H    1-AI-Pip(4) 498  H   H   (CH 2) 2OH    3-Hx    H    1-AI-Pip(4) 499  H   H   (CH 2) 2OH    2-CF 3  H    1-AI-Pip(4) 500  H   H  (CH 2) 2OH    3-CF 3        H    1-AI-Pip(4) 501  H   H  (CH 2) 2OH    2-OMe         H    1-AI-Pip(4) 502  H   H  (CH 2) 2OH    3-OMe         H    1-AI-Pip(4) 503  H   H  (CH 2) 2OH    2-OEt         H    1-AI-Pip(4) 504  H   H  (CH 2) 2OH    3-OEt         H    1-AI-Pip(4) 505  H   H  (CH 2) 2OH    2-COOH        H    1-AI-Pip(4) 506  H   H  (CH 2) 2OH    3-COOH        H    1-AI-Pip(4) 507  H   H  (CH 2) 2OH    2-COOMe       H    1-AI-Pip(4) 508  H   H  (CH 2) 2OH    3-COOMe       H    1-AI-Pip(4) 509  H   H  (CH 2) 2OH    2-COOEt       H    1-AI-Pip(4) 510  H   H  (CH 2) 2OH    3-COOEt       H    1-AI-Pip(4) 511  H   H  (CH 2) 2OH    2-COOPr       H    1-AI-Pip(4) 512  H   H  (CH 2) 2OH    3-COOPr       H    1-AI-Pip(4) 513  H   H  (CH 2) 2OH    2-COOBu       H    1-AI-Pip(4) 514  H   H  (CH 2) 2OH    3-COOBu       H    1-AI-Pip(4) 515  H   H  (CH 2) 2OH    2-COOPn       H    1-AI-Pip(4) 516  H   H  (CH 2) 2OH    3-COOPn       H    1-AI-Pip(4) 517  H   H  (CH 2) 2OH    2-COOHx       H    1-AI-Pip(4) 518  H   H  (CH 2) 2OH    3-COOHx       H    1-AI-Pip(4) 519  H   H  (CH 2) 2OH    2-CONH 2      H    1-AI-Pip(4) 520  H   H  (CH 2) 2OH    3-CONH 2      H    1-AI-Pip(4) 521  H   H  (CH 2) 2OH    2-CONHMe      H    1-AI-Pip(4) 522  H   H  (CH 2) 2OH    3-CONHMe      H    1-AI-Pip(4) 523  H   H  (CH 2) 2OH    2-CONHEt      H    1-AI-Pip(4) 524  H   H  (CH 2) 2OH    3-CONHEt      H    1-AI-Pip(4) 525  H   H  (CH 2) 2OH    2-CON(Me) 2   H    1-AI-Pip(4) 526  H   H  (CH 2) 2OH    3-CON(Me) 2   H    1-AI-Pip(4) 527  H   H  (CH 2) 2OH    2-CON(Me)Et   H    1-AI-Pip(4) 528  H   H  (CH 2) 2OH    3-CON(Me)Et   H    1-AI-Pip(4) 529  H    H    (CH 2) 2OH    2-CON(Et) 2  H        1-AI-Pip(4) 530  H    H    (CH 2) 2OH    3-CON(Et) 2  H        1-AI-Pip(4) 531  H    H    (CH 2) 2OH    3-F          5-F      1-AI-Pip(4) 532  H    H    (CH 2) 2OH    3-Cl         5-Cl     1-AI-Pip(4) 533  H    H    (CH 2) 2OH    3-Me         5-Me     1-AI-Pip(4) 534  H    H    (CH 2) 2OH    3-Cl         5-NH 2   1-AI-Pip(4) 535  H    H    (CH 2) 2OH    2-Me         5-CONH 2 1-AI-Pip(4) 536  H    H    (CH 2) 2OH    3-Me         5-CONH 2 1-AI-Pip(4) 537  H    H    (CH 2) 2OH    3-CONH 2     5-CONH 2 1-AI-Pip(4) 538  H    H    (CH 2) 3OH    H            H        1-AI-Pip(4) 539  H    H    (CH 2) 4OH    H            H        1-AI-Pip(4) 540  H    H    (CH 2) 5OH    H            H        1-AI-Pip(4) 541  H    H    (CH 2) 6OH    H            H        1-AI-Pip(4) 542  H    H    CH 2COOH      H            H        1-AI-Pip(4) 543  H    H    CH 2COOH      2-F          H        1-AI-Pip(4) 544  H    H    CH 2COOH      3-F          H        1-AI-Pip(4) 545  H    H    CH 2COOH      2-Cl         H        1-AI-Pip(4) 546  H    H    CH 2COOH      3-Cl         H        1-AI-Pip(4) 547  H    H    CH 2COOH      2-Br         H        1-AI-Pip(4) 548  H    H    CH 2COOH      3-Br         H        1-AI-Pip(4) 549  H    H    CH 2COOH      2-I          H        1-AI-Pip(4) 550  H    H    CH 2COOH      3-I          H        1-AI-Pip(4) 551  H    H    CH 2COOH      2-Me         H        1-AI-Pip(4) 552  H    H    CH 2COOH      3-Me         H        1-AI-Pip(4) 553  H    H    CH 2COOH      2-Et         H        1-AI-Pip(4) 554  H    H    CH 2COOH      3-Et         H        1-AI-Pip(4) 555  H    H    CH 2COOH      2-Pr         H        1-AI-Pip(4) 556  H    H    CH 2COOH      3-Pr         H        1-AI-Pip(4) 557  H    H    CH 2COOH      2-Bu         H        1-AI-Pip(4) 558  H    H   CH 2COOH    3-Bu        H    1-AI-Pip(4) 559  H    H   CH 2COOH    2-Pr        H    1-AI-Pip(4) 560  H    H   CH 2COOH    3-Pn        H    1-AI-Pip(4) 561  H    H   CH 2COOH    2-Hx        H    1-AI-Pip(4) 562  H    H   CH 2COOH    3-Hx        H    1-AI-Pip(4) 563  H    H   CH 2COOH    2-CF 3      H    1-AI-Pip(4) 564  H    H   CH 2COOH    3-CF 3      H    1-AI-Pip(4) 565  H    H   CH 2COOH    2-OMe       H    1-AI-Pip(4) 566  H    H   CH 2COOH    3-OMe       H    1-AI-Pip(4) 567  H    H   CH 2COOH    2-OEt       H    1-AI-Pip(4) 568  H    H   CH 2COOH    3-OEt       H    1-AI-Pip(4) 569  H    H   CH 2COOH    2-COOH      H    1-AI-Pip(4) 570  H    H   CH 2COOH    3-COOH      H    1-AI-Pip(4) 571  H    H   CH 2COOH    2-COOMe     H    1-AI-Pip(4) 572  H    H   CH 2COOH    3-COOMe     H    1-AI-Pip(4) 573  H    H   CH 2COOH    2-COOEt     H    1-AI-Pip(4) 574  H    H   CH 2COOH    3-COOEt     H    1-AI-Pip(4) 575  H    H   CH 2COOH    2-COOPr     H    1-AI-Pip(4) 576  H    H   CH 2COOH    3-COOPr     H    1-AI-Pip(4) 577  H    H   CH 2COOH    2-COOBu     H    1-AI-Pip(4) 578  H    H   CH 2COOH    3-COOBu     H    1-AI-Pip(4) 579  H    H   CH 2COOH    2-COOPn     H    1-AI-Pip(4) 580  H    H   CH 2COOH    3-COOPn     H    1-AI-Pip(4) 581  H    H   CH 2COOH    2-COOHx     H    1-AI-Pip(4) 582  H    H   CH 2COOH    3-COOHx     H    1-AI-Pip(4) 583  H    H   CH 2COOH    2-CONH 2    H    1-AI-Pip(4) 584  H    H   CH 2COOH    3-CONH 2    H    1-AI-Pip(4) 585  H    H   CH 2COOH    2-CONHMe    H    1-AI-Pip(4) 586  H    H   CH 2COOH    3-CONHMe    H    1-AI-Pip(4) 587  H      H  CH 2COOH    2-CONHEt     H           1-AI-Pip(4) 588  H      H  CH 2COOH    3-CONHEt     H           1-AI-Pip(4) 589  H      H  CH 2COOH    2-CON(Me) 2  H           1-AI-Pip(4) 590  H      H  CH 2COOH    3-CON9(Me) 2 H           1-AI-Pip(4) 591  H      H  CH 2COOH    2-CON(Me)Et  H           1-AI-Pip(4) 592  H      H  CH 2COOH    3-CON(Me)Et  H           1-AI-Pip(4) 593  H      H  CH 2COOH    2-CON(Et) 2  H           1-AI-Pip(4) 594  H      H  CH 2COOH    3-CON(Et) 2  H           1-AI-Pip(4) 595  H      H  CH 2COOH    3-F          5-F         1-AI-Pip(4) 596  H      H  CH 2COOH    3-Cl         5-Cl        1-AI-Pip(4) 597  H      H  CH 2COOH    3-Me         5-Me        1-AI-Pip(4) 598  H      H  CH 2COOH    3-Cl         5-CONH 2    1-AI-Pip(4) 599  H      H  CH 2COOH    2-Me         5-CONH 2    1-AI-Pip(4) 600  H      H  CH 2COOH    3-Me         5-CONH 2    1-AI-Pip(4) 601  H      H  CH 2COOH    3-CONH 2     5-CONH 2    1-AI-Pip(4) 602  6-OH   H  CH 2COOH    H            H           1-AI-Pip(4) 603  6-OH   H  CH 2COOH    2-F          H           1-AI-Pip(4) 604  6-OH   H  CH 2COOH    3-F          H           1-AI-Pip(4) 605  6-OH   H  CH 2COOH    2-Cl         H           1-AI-Pip(4) 606  6-OH   H  CH 2COOH    3-Cl         H           1-AI-Pip(4) 607  6-OH   H  CH 2COOH    2-Br         H           1-AI-Pip(4) 608  6-OH   H  CH 2COOH    3-Br         H           1-AI-Pip(4) 609  6-OH   H  CH 2COOH    2-I          H           1-AI-Pip(4) 610  6-OH   H  CH 2COOH    3-I          H           1-AI-Pip(4) 611  6-OH   H  CH 2COOH    2-Me         H           1-AI-Pip(4) 612  6-OH   H  CH 2COOH    3-Me         H           1-AI-Pip(4) 613  6-OH   H  CH 2COOH    2-Et         H           1-AI-Pip(4) 614  6-OH   H  CH 2COOH    3-Et         H           1-AI-Pip(4) 615  6-OH   H  CH 2COOH    2-Pr         H           1-AI-Pip(4) 616  6-OH    H    CH 2COOH    3-Pr       H    1-AI-Pip(4) 617  6-OH    H    CH 2COOH    2-Bu       H    1-AI-Pip(4) 618  6-OH    H    CH 2COOH    3-Bu       H    1-AI-Pip(4) 619  6-OH    H    CH 2COOH    2-Pn       H    1-AI-Pip(4) 620  6-OH    H    CH 2COOH    3-Pn       H    1-AI-Pip(4) 621  6-OH    H    CH 2COOH    2-Hx       H    1-AI-Pip(4) 622  6-OH    H    CH 2COOH    3-Hx       H    1-AI-Pip(4) 623  6-OH    H    CH 2COOH    2-CF 3     H    1-AI-Pip(4) 624  6-OH    H    CH 2COOH    3-CF 3     H    1-AI-Pip(4) 625  6-OH    H    CH 2COOH    2-OMe      H    1-AI-Pip(4) 626  6-OH    H    CH 2COOH    3-OMe      H    1-AI-Pip(4) 627  6-OH    H    CH 2COOH    2-OEt      H    1-AI-Pip(4) 628  6-OH    H    CH 2COOH    3-OEt      H    1-AI-Pip(4) 629  6-OH    H    CH 2COOH    2-COOH     H    1-AI-Pip(4) 630  6-OH    H    CH 2COOH    3-COOH     H    1-AI-Pip(4) 631  6-OH    H    CH 2COOH    2-COOMe    H    1-AI-Pip(4) 632  6-OH    H    CH 2COOH    3-COOMe    H    1-AI-Pip(4) 633  6-OH    H    CH 2COOH    2-COOEt    H    1-AI-Pip(4) 634  6-OH    H    CH 2COOH    3-COOEt    H    1-AI-Pip(4) 635  6-OH    H    CH 2COOH    2-COOPr    H    1-AI-Pip(4) 636  6-OH    H    CH 2COOH    3-COOPr    H    1-AI-Pip(4) 637  6-OH    H    CH 2COOH    2-COOBu    H    1-AI-Pip(4) 638  6-OH    H    CH 2COOH    3-COOBu    H    1-AI-Pip(4) 639  6-OH    H    CH 2COOH    2-COOPn    H    1-AI-Pip(4) 640  6-OH    H    CH 2COOH    3-COOPn    H    1-AI-Pip(4) 641  6-OH    H    CH 2COOH    2-COOHx    H    1-AI-Pip(4) 642  6-OH    H    CH 2COOH    3-COOHx    H    1-AI-Pip(4) 643  6-OH    H    CH 2COOH    2-CONH 2   H    1-AI-Pip(4) 644  6-OH    H    CH 2COOH    3-CONH 2   H    1-AI-Pip(4) 645  6-OH   H  CH 2COOH       2-CONHMe      H         1-AI-Pip(4) 646  6-OH   H  CH 2COOH       3-CONHMe      H         1-AI-Pip(4) 647  6-OH   H  CH 2COOH       2-CONHEt      H         1-AI-Pip(4) 648  6-OH   H  CH 2COOH       3-CONHEt      H         1-AI-Pip(4) 649  6-OH   H  CH 2COOH       2-CON(Me) 2   H         1-AI-Pip(4) 650  6-OH   H  CH 2COOH       3-CON(Me) 2   H         1-AI-Pip(4) 651  6-OH   H  CH 2COOH       2-CON(Me)Et   H         1-AI-Pip(4) 652  6-OH   H  CH 2COOH       3-CON(Et)Et   H         1-AI-Pip(4) 653  6-OH   H  CH 2COOH       2-CON(Et) 2   H         1-AI-Pip(4) 654  6-OH   H  CH 2COOH       3-CON(Et) 2   H         1-AI-Pip(4) 655  6-OH   H  CH 2COOH       3-F           5-F       1-AI-Pip(4) 656  6-OH   H  CH 2COOH       3-Cl          5-Cl      1-AI-Pip(4) 657  6-OH   H  CH 2COOH       3-Me          5-Me      1-AI-Pip(4) 658  6-OH   H  CH 2COOH       3-Cl          5-CONH 2  1-AI-Pip(4) 659  6-OH   H  CH 2COOH       2-Me          5-CONH 2  1-AI-Pip(4) 660  6-OH   H  CH 2COOH       3-Me          5-CONH 2  1-AI-Pip(4) 661  6-OH   H  CH 2COOH       3-CONH 2      5-CONH 2  1-AI-Pip(4) 662  H      H  (CH 2) 2COOH   H             H         1-AI-Pip(4) 663  H      H  (CH 2) 3COOH   H             H         1-AI-Pip(4) 664  H      H  (CH 2) 4COOH   H             H         1-AI-Pip(4) 665  H      H  (CH 2) 5COOH   H             H         1-AI-Pip(4) 666  H      H  (CH 2) 6COOH   H             H         1-AI-Pip(4) 667  H      H  CH 2COOMe      H             H         1-AI-Pip(4) 668  H      H  CH 2COOEt      H             H         1-AI-Pip(4) 669  H      H  CH 2COOEt      2-F           H         1-AI-Pip(4) 670  H      H  CH 2COOEt      3-F           H         1-AI-Pip(4) 671  H      H  CH 2COOEt      2-Cl          H         1-AI-Pip(4) 672  H      H  CH 2COOEt      3-Cl          H         1-AI-Pip(4) 673  H      H  CH 2COOEt      2-Br          H         1-AI-Pip(4) 674  H    H    CH 2COOEt    3-Br       H    1-AI-Pip(4) 675  H    H    CH 2COOEt    2-I        H    1-AI-Pip(4) 676  H    H    CH 2COOEt    3-I        H    1-AI-Pip(4) 677  H    H    CH 2COOEt    2-Me       H    1-AI-Pip(4) 678  H    H    CH 2COOEt    3-Me       H    1-AI-Pip(4) 679  H    H    CH 2COOEt    2-Et       H    1-AI-Pip(4) 680  H    H    CH 2COOET    3-Et       H    1-AI-Pip(4) 681  H    H    CH 2COOEt    2-Pr       H    1-AI-Pip(4) 682  H    H    CH 2COOEt    3-Pr       H    1-AI-Pip(4) 683  H    H    CH 2COOEt    2-Bu       H    1-AI-Pip(4) 684  H    H    CH 2COOEt    3-Bu       H    1-AI-Pip(4) 685  H    H    CH 2COOEt    2-Pn       H    1-AI-Pip(4) 686  H    H    CH 2COOEt    3-Pn       H    1-AI-Pip(4) 687  H    H    CH 2COOEt    2-Hx       H    1-AI-Pip(4) 688  H    H    CH 2COOEt    3-Hx       H    1-AI-Pip(4) 689  H    H    CH 2COOEt    2-CF 3     H    1-AI-Pip(4) 690  H    H    CH 2COOEt    3-CF 3     H    1-AI-Pip(4) 691  H    H    CH 2COOEt    2-OMe      H    1-AI-Pip(4) 692  H    H    CH 2COOEt    3-OMe      H    1-AI-Pip(4) 693  H    H    CH 2COOEt    2-OEt      H    1-AI-Pip(4) 694  H    H    CH 2COOEt    3-OEt      H    1-AI-Pip(4) 695  H    H    CH 2COOEt    2-COOH     H    1-AI-Pip(4) 696  H    H    CH 2COOEt    3-COOH     H    1-AI-Pip(4) 697  H    H    CH 2COOEt    2-COOMe    H    1-AI-Pip(4) 698  H    H    CH 2COOEt    3-COOMe    H    1-AI-Pip(4) 699  H    H    CH 2COOEt    2-COOEt    H    1-AI-Pip(4) 700  H    H    CH 2COOEt    3-COOEt    H    1-AI-Pip(4) 701  H    H    CH 2COOEt    2-COOPr    H    1-AI-Pip(4) 702  H    H    CH 2COOEt    3-COOPr    H    1-AI-Pip(4) 703  H       H   CH 2COOEt    2-COOBu        H        1-AI-Pip(4) 704  H       H   CH 2COOEt    3-COOBu        H        1-AI-Pip(4) 705  H       H   CH 2COOEt    2-COOPn        H        1-AI-Pip(4) 706  H       H   CH 2COOEt    3-COOPn        H        1-AI-Pip(4) 707  H       H   CH 2COOEt    2-COOHx        H        1-AI-Pip(4) 708  H       H   CH 2COOEt    3-COOHx        H        1-AI-Pip(4) 709  H       H   CH 2COOEt    2-CONH 2       H        1-AI-Pip(4) 710  H       H   CH 2COOEt    3-CONH 2       H        1-AI-Pip(4) 711  H       H   CH 2COOEt    2-CONHMe       H        1-AI-Pip(4) 712  H       H   CH 2COOEt    3-CONHMe       H        1-AI-Pip(4) 713  H       H   CH 2COOEt    2-OONHEt       H        1-AI-Pip(4) 714  H       H   CH 2COOEt    3-CONHEt       H        1-AI-Pip(4) 715  H       H   CH 2COOEt    2-CON(Me) 2    H        1-AI-Pip(4) 716  H       H   CH 2COOEt    3-CON(Me) 2    H        1-AI-Pip(4) 717  H       H   CH 2COOEt    2-CON(Me)Et    H        1-AI-Pip(4) 718  H       H   CH 2COOEt    3-CON(Me)Et    H        1-AI-Pip(4) 719  H       H   CH 2COOEt    2-CON(Et) 2    H        1-AI-Pip(4) 720  H       H   CH 2COOEt    3-CON(ET) 2    H        1-AI-Pip(4) 721  H       H   CH 2COOEt    3-F            5-F      1-AI-Pip(4) 722  H       H   CH 2COOEt    3-Cl           5-Cl     1-AI-Pip(4) 723  H       H   CH 2COOEt    3-Me           5-Me     1-AI-Pip(4) 724  H       H   CH 2COOEt    3-Cl           5-CONH 2 1-AI-Pip(4) 725  H       H   CH 2COOEt    2-Me           5-CONH 2 1-AI-Pip(4) 726  H       H   CH 2COOEt    3-Me           5-CONH 2 1-AI-Pip(4) 727  H       H   CH 2COOEt    3-CONH 2       5-CONH 2 1-AI-Pip(4) 728  6-OHOH  H   CH 2COOEt    H              H        1-AI-Pip(4) 729  6-OH    H   CH 2COOEt    2-F            H        1-AI-Pip(4) 730  6-OH    H   CH 2COOEt    3-F            H        1-AI-Pip(4) 731  6-OH    H   CH 2COOEt    2-Cl           H        1-AI-Pip(4) 732 6-OH    H    CH 2COOEt    3-Cl      H    1-AI-Pip(4) 733 6-OH    H    CH 2COOEt    2-Br      H    1-AI-Pip(4) 734 6-OH    H    CH 2COOEt    3-Br      H    1-AI-Pip(4) 735 6-OH    H    CH 2COOEt    2-I       H    1-AI-Pip(4) 736 6-OH    H    CH 2COOEt    3-I       H    1-AI-Pip(4) 737 6-OH    H    CH 2COOEt    2-Me      H    1-AI-Pip(4) 738 6-OH    H    CH 2COOEt    3-Me      H    1-AI-Pip(4) 739 6-OH    H    CH 2COOEt    2-Et      H    1-AI-Pip(4) 740 6-OH    H    CH 2COOEt    3-Et      H    1-AI-Pip(4) 741 6-OH    H    CH 2COOEt    2-Pr      H    1-AI-Pip(4) 742 6-OH    H    CH 2COOEt    3-Pr      H    1-AI-Pip(4) 743 6-OH    H    CH 2COOEt    2-Bu      H    1-AI-Pip(4) 744 6-OH    H    CH 2COOEt    3-Bu      H    1-AI-Pip(4) 745 6-OH    H    CH 2COOEt    2-Pn      H    1-AI-Pip(4) 746 6-OH    H    CH 2COOEt    3-Pn      H    1-AI-Pip(4) 747 6-OH    H    CH 2COOEt    2-Hx      H    1-AI-Pip(4) 748 6-OH    H    CH 2COOEt    3-Hx      H    1-AI-Pip(4) 749 6-OH    H    CH 2COOEt    2-CF 3    H    1-AI-Pip(4) 750 6-OH    H    CH 2COOEt    3-CF 3    H    1-AI-Pip(4) 751 6-OH    H    CH 2COOEt    2-OMe     H    1-AI-Pip(4) 752 6-OH    H    CH 2COOEt    3-OMe     H    1-AI-Pip(4) 753 6-OH    H    CH 2COOEt    2-OEt     H    1-AI-Pip(4) 754 6-OH    H    CH 2COOEt    3-OEt     H    1-AI-Pip(4) 755 6-OH    H    CH 2COOEt    2-COOH    H    1-AI-Pip(4) 756 6-OH    H    CH 2COOEt    3-COOH    H    1-AI-Pip(4) 757 6-OH    H    CH 2COOEt    2-COOMe   H    1-AI-Pip(4) 758 6-OH    H    CH 2COOEt    3-COOMe   H    1-AI-Pip(4) 759 6-OH    H    CH 2COOEt    2-COOEt   H    1-AI-Pip(4) 760 6-OH    H    CH 2COOEt    3-COOEt   H    1-AI-Pip(4) 761  6-OH    H    CH 2COOEt        2-COOPr         H          1-AI-Pip(4) 762  6-OH    H    CH 2COOEt        3-COOPr         H          1-AI-Pip(4) 763  6-OH    H    CH 2COOEt        2-COOBu         H          1-AI-Pip(4) 764  6-OH    H    CH 2COOEt        3-COOBu         H          1-AI-Pip(4) 765  6-OH    H    CH 2COOEt        2-COOPn         H          1-AI-Pip(4) 766  6-OH    H    CH 2COOEt        3-COOPn         H          1-AI-Pip(4) 767  6-OH    H    CH 2COOEt        2-COOHx         H          1-AI-Pip(4) 768  6-OH    H    CH 2COOEt        3-COOHx         H          1-AI-Pip(4) 769  6-OH    H    CH 2COOEt        2-CONH 2        H          1-AI-Pip(4) 770  6-OH    H    CH 2COOEt        3-CONHx         H          1-AI-Pip(4) 771  6-OH    H    CH 2COOEt        2-CONHMe        H          1-AI-Pip(4) 772  6-OH    H    CH 2COOEt        3-CONHMe        H          1-AI-Pip(4) 773  6-OH    H    CH 2COOEt        2-CONHEt        H          1-AI-Pip(4) 774  6-OH    H    CH 2COOEt        3-CONHEt        H          1-AI-Pip(4) 775  6-OH    H    CH 2COOEt        2-CON(Me) 2     H          1-AI-Pip(4) 776  6-OH    H    CH 2COOEt        3-CON(Me) 2     H          1-AI-Pip(4) 777  6-OH    H    CH 2COOEt        2-CON(Me)Et     H          1-AI-Pip(4) 778  6-OH    H    CH 2COOEt        3-CON(Me)Et     H          1-AI-Pip(4) 779  6-OH    H    CH 2COOEt        2-CON(Et) 2     H          1-AI-Pip(4) 780  6-OH    H    CH 2COOEt        3-CON(Et) 2     H          1-AI-Pip(4) 781  6-OH    H    CH 2COOEt        3-F             5-F        1-AI-Pip(4) 782  6-OH    H    CH 2COOEt        3-Cl            5-Cl       1-AI-Pip(4) 783  6-OH    H    CH 2COOEt        3-Me            5-Me       1-AI-Pip(4) 784  6-OH    H    CH 2COOEt        3-Cl            5-CONH 2   1-AI-Pip(4) 785  6-OH    H    CH 2COOEt        2-Me            5-CONH 2   1-AI-Pip(4) 786  6-OH    H    CH 2COOEt        3-Me            5-CONH 2   1-AI-Pip(4) 787  6-OH    H    CH 2COOEt        3-CONH 2        5-CONH 2   1-AI-Pip(4) 788  H       H    CH(CH 3)COOEt    H               H          1-AI-Pip(4) 789  H       H    CH(CH 3)COOEt    2-F             H          1-AI-Pip(4) 790  H    H   CH(CH 3)COOEt    3-F       H    1-AI-Pip(4) 791  H    H   CH(CH 3)COOEt    2-Cl      H    1-AI-Pip(4) 792  H    H   CH(CH 3)COOEt    3-Cl      H    1-AI-Pip(4) 793  H    H   CH(CH 3)COOEt    2-Br      H    1-AI-Pip(4) 794  H    H   CH(CH 3)COOEt    3-Br      H    1-AI-Pip(4) 795  H    H   CH(CH 3)COOEt    2-I       H    1-AI-Pip(4) 796  H    H   CH(CH 3)COOEt    3-I       H    1-AI-Pip(4) 797  H    H   CH(CH 3)COOEt    2-Me      H    1-AI-Pip(4) 798  H    H   CH(CH 3)COOEt    3-Me      H    1-AI-Pip(4) 799  H    H   CH(CH 3)COOEt    2-Et      H    1-AI-Pip(4) 800  H    H   CH(CH 3)COOEt    3-Et      H    1-AI-Pip(4) 801  H    H   CH(CH 3)COOEt    2-Pr      H    1-AI-Pip(4) 802  H    H   CH(CH 3)COOEt    3-Pr      H    1-AI-Pip(4) 803  H    H   CH(CH 3)COOEt    2-Bu      H    1-AI-Pip(4) 804  H    H   CH(CH 3)COOEt    3-Bu      H    1-AI-Pip(4) 805  H    H   CH(CH 3)COOEt    2-Pn      H    1-AI-Pip(4) 806  H    H   CH(CH 3)COOEt    3-Pn      H    1-AI-Pip(4) 807  H    H   CH(CH 3)COOEt    2-Hx      H    1-AI-Pip(4) 808  H    H   CH(CH 3)COOEt    3-Hx      H    1-AI-Pip(4) 809  H    H   CH(CH 3)COOEt    2-CF 3    H    1-AI-Pip(4) 810  H    H   CH(CH 3)COOEt    3-CF 3    H    1-AI-Pip(4) 811  H    H   CH(CH 3)COOEt    2-OMe     H    1-AI-Pip(4) 812  H    H   CH(CH 3)COOEt    3-OMe     H    1-AI-Pip(4) 813  H    H   CH(CH 3)COOEt    2-OEt     H    1-AI-Pip(4) 814  H    H   CH(CH 3)COOEt    3-OEt     H    1-AI-Pip(4) 815  H    H   CH(CH 3)COOEt    2-COOH    H    1-AI-Pip(4) 816  H    H   CH(CH 3)COOEt    3-COOH    H    1-AI-Pip(4) 817  H    H   CH(CH 3)COOEt    2-COOMe   H    1-AI-Pip(4) 818  H    H   CH(CH 3)COOEt    3-COOMe   H    11-AI-Pip(4) 819  H   H   CH(CH 3)COOEt   2-COOEt       H         1-AI-Pip(4) 820  H   H   CH(CH 3)COOEt   3-COOEt       H         1-AI-Pip(4) 821  H   H   CH(CH 3)COOEt   2-COOPr       H         1-AI-Pip(4) 822  H   H   CH(CH 3)COOEt   3-COOPr       H         1-AI-Pip(4) 823  H   H   CH(CH 3)COOEt   2-COOBu       H         1-AI-Pip(4) 824  H   H   CH(CH 3)COOEt   3-COOBu       H         1-AI-Pip(4) 825  H   H   CH(CH 3)COOEt   2-COOPn       H         1-AI-Pip(4) 826  H   H   CH(CH 3)COOEt   3-COOPn       H         1-AI-Pip(4) 827  H   H   CH(CH 3)COOEt   2-COOHx       H         1-AI-Pip(4) 828  H   H   CH(CH 3)COOEt   3-COOHx       H         1-AI-Pip(4)  829 H   H   CH(CH 3)COOEt   2-CONH 2      H         1-AI-Pip(4) 830  H   H   CH(CH 3)COOEt   3-CONH 2      H         1-AI-Pip(4) 831  H   H   CH(CH 3)COOEt   2-CONHMe      H         1-AI-Pip(4) 832  H   H   CH(CH 3)COOEt   3-CONHMe      H         1-AI-Pip(4) 833  H   H   CH(CH 3)COOEt   2-CONHEt      H         1-AI-Pip(4) 834  H   H   CH(CH 3)COOEt   3-CONHEt      H         1-AI-Pip(4) 835  H   H   CH(CH 3)COOEt   2-CON(Me) 2   H         1-AI-Pip(4) 836  H   H   CH(CH 3)COOEt   3-CON(Me) 2   H         1-AI-Pip(4) 837  H   H   CH(CH 3)COOEt   2-CON(Me)Et   H         1-AI-Pip(4) 838  H   H   CH(CH 3)COOEt   3-CON(Me)Et   H         1-AI-Pip(4) 839  H   H   CH(CH 3)COOEt   2-CON(Et) 2   H         1-AI-Pip(4) 840  H   H   CH(CH 3)COOEt   3-CON(Et) 2   H         1-AI-Pip(4) 841  H   H   CH(CH 3)COOEt   3-F           5-F       1-AI-Pip(4) 842  H   H   CH(CH 3)COOEt   3-Cl          5-Cl      1-AI-Pip(4) 843  H   H   CH(CH 3)COOEt   3-Me          5-Me      1-AI-Pip(4) 844  H   H   CH(CH 3)COOEt   3-Cl          5-CONH 2  1-AI-Pip(4) 845  H   H   CH(CH 3)COOEt   2-Me          5-CONH 2  1-AI-Pip(4) 846  H   H   CH(CH 3)COOEt   3-Me          5-CONH 2  1-AI-Pip(4) 847  H   H   CH(CH 3)COOEt   3-CONH 2      5-CONH 2  1-AI-Pip(4) 848  H   H   (CH 2) 2COOEt        H       H    1-AI-Pip(4) 849  H   H   (CH 2) 3COOEt        H       H    1-AI-Pip(4) 850  H   H   (CH 2) 4COOEt        H       H    1-AI-Pip(4) 851  H   H   (CH 2) 5COOEt        H       H    1-AI-Pip(4) 852  H   H   (CH 2) 6COOEt        H       H    1-AI-Pip(4) 853  H   H   CH 2COCH 2COOMe      H       H    1-AI-Pip(4) 854  H   H   CH 2COCH 2COOEt      H       H    1-AI-Pip(4) 855  H   H   CH 2COCH 2COOPr      H       H    1-AI-Pip(4) 856  H   H   CH 2COCH 2COOBu      H       H    1-AI-Pip(4) 857  H   H   CH 2COCH 2COOPn      H       H    1-AI-Pip(4) 858  H   H   CH 2COCH 2COOHx      H       H    1-AI-Pip(4) 859  H   H   (CH 2) 2COCH 2COOEt  H       H    1-AI-Pip(4) 860  H   H   (CH 2) 3COCH 2COOEt  H       H    1-AI-Pip(4) 861  H   H   (CH 2) 4COCH 2COOEt  H       H    1-AI-Pip(4) 862  H   H   (CH 2) 5CH 2COOEt    H       H    1-AI-Pip(4) 863  H   H   (CH 2) 6COCH 2COOEt  H       H    1-AI-Pip(4) 864  H   H   Bn                    H       H    1-AI-Pip(4) 865  H   H   Bn                    2-F     H    1-AI-Pip(4) 866  H   H   Bn                    3-F     H    1-AI-Pip(4) 867  H   H   Bn                    2-Br    H    1-AI-Pip(4) 868  H   H   Bn                    3-Cl    H    1-AI-Pip(4) 869  H   H   Bn                    2-Br    H    1-AI-Pip(4) 870  H   H   Bn                    3-Br    H    1-AI-Pip(4) 871  H   H   Bn                    2-I     H    1-AI-Pip(4) 872  H   H   Bn                    3-I     H    1-AI-Pip(4) 873  H   H   Bn                    2-Me    H    1-AI-Pip(4) 874  H   H   Bn                    3-Me    H    1-AI-Pip(4) 875  H   H   Bn                    2-Et    H    1-AI-Pip(4) 876  H   H   Bn                    3-Et    H    1-AI-Pip(4) 877  H   H   Bn    2-Pr      H   1-AI-Pip(4) 878  H   H   Bn    3-Pr      H   1-AI-Pip(4) 879  H   H   Bn    2-Bu      H   1-AI-Pip(4) 880  H   H   Bn    3-Bu      H   1-AI-Pip(4) 881  H   H   Bn    2-Pn      H   1-AI-Pip(4) 882  H   H   Bn    3-Pn      H   1-AI-Pip(4) 883  H   H   Bn    2-Hx      H   1-AI-Pip(4) 884  H   H   Bn    3-Hx      H   1-AI-Pip(4) 885  H   H   Bn    2-CF 3    H   1-AI-Pip(4) 886  H   H   Bn    3-CF 3    H   1-AI-Pip(4) 887  H   H   Bn    2-OMe     H   1-AI-Pip(4) 888  H   H   Bn    3-OMe     H   1-AI-Pip(4) 889  H   H   Bn    2-OEt     H   1-AI-Pip(4) 890  H   H   Bn    3-OEt     H   1-AI-Pip(4) 891  H   H   Bn    2-COOH    H   1-AI-Pip(4) 892  H   H   Bn    3-COOH    H   1-AI-Pip(4) 893  H   H   Bn    2-COOMe   H   1-AI-Pip(4) 894  H   H   Bn    3-COOMe   H   1-AI-Pip(4) 895  H   H   Bn    2-COOEt   H   1-AI-Pip(4) 896  H   H   Bn    3-COOEt   H   1-AI-Pip(4) 897  H   H   Bn    2-COOPr   H   1-AI-Pip(4) 898  H   H   Bn    3-COOPr   H   1-AI-Pip(4) 899  H   H   Bn    2-COOBu   H   1-AI-Pip(4) 900  H   H   Bn    3-COOBu   H   1-AI-Pip(4) 901  H   H   Bn    2-COOPn   H   1-AI-Pip(4) 902  H   H   Bn    3-COOPn   H   1-AI-Pip(4) 903  H   H   Bn    2-COOHx   H   1-AI-Pip(4) 904  H   H   Bn    3-COOHx   H   1-AI-Pip(4) 905  H   H   Bn    2-CONH 2  H   1-AI-Pip(4) 906  H     H   Bn             3-CONH 2      H         1-AI-Pip(4) 907  H     H   Bn             2-CONHMe      H         1-AI-Pip(4) 908  H     H   Bn             3-CONHMe      H         1-AI-Pip(4) 909  H     H   Bn             2-CONHEt      H         1-AI-Pip(4) 910  H     H   Bn             3-CONHEt      H         1-AI-Pip(4) 911  H     H   Bn             2-CON(Me) 2   H         1-AI-Pip(4) 912  H     H   Bn             3-CON(Me) 2   H         1-AI-Pip(4) 913  H     H   Bn             2-CON(Me)Et   H         1-AI-Pip(4) 914  H     H   Bn             3-CON(Me)Et   H         1-AI-Pip(4) 915  H     H   Bn             2-CON(Et) 2   H         1-AI-Pip(4) 916  H     H   Bn             3-CON(Et) 2   H         1-AI-Pip(4) 917  H     H   Bn             3-F           5-F       1-AI-Pip(4) 918  H     H   Bn             3-Cl          5-Cl      1-AI-Pip(4) 919  H     H   Bn             3-Me          5-Me      1-AI-Pip(4) 920  H     H   Bn             3-Cl          5-CONH 2  1-AI-Pip(4) 921  H     H   Bn             2-Me          5-CONH 2  1-AI-Pip(4) 922  H     H   Bn             3-Me          5-CONH 2  1-AI-Pip(4) 923  H     H   Bn             3-CONH 2      5-CONH 2  1-AI-Pip(4) 924  H     H   CH 2Np(1)      H             H         1-AI-Pip(4) 925  6-OH  H   CH 2Np(1)      H             H         1-AI-Pip(4) 926  H     H   CH 2Np(2)      H             H         1-AI-Pip(4) 927  6-OH  H   CH 2Np(2)      H             H         1-AI-Pip(4) 928  H     H   (CH 2) 2Ph     H             H         1-AI-Pip(4) 929  6-OH  H   (CH 2) 2Ph     H             H         1-AI-Pip(4) 930  H     H   (CH 2) 2Np(1)  H             H         1-AI-Pip(4) 931  6-OH  H   (CH 2) 2Np(1)  H             H         1-AI-Pip(4) 932  H     H   (CH 2) 2Np(2)  H             H         1-AI-Pip(4) 933  6-OH  H   (CH 2) 2Np(2)  H             H         1-AI-Pip(4) 934  H     H   (CH 2) 3Ph     H             H         1-AI-Pip(4) 935  6-OH  H   (CH 2) 3Ph     H      H    1-AI-Pip(4) 936  H     H   (CH 2) 3Np(1)  H      H    1-AI-Pip(4) 937  6-OH  H   (CH 2) 2Np(1)  H      H    1-AI-Pip(4) 938  H     H   (CH 2) 3Np(2)  H      H    1-AI-Pip(4) 939  6-OH  H   (CH 2) 3Np(2)  H      H    1-AI-Pip(4) 940  H     H   (CH 2) 4Ph     H      H    1-AI-Pip(4) 941  6-OH  H   (CH 2) 4Ph     H      H    1-AI-Pip(4) 942  H     H   (CH 2) 5Ph     H      H    1-AI-Pip(4) 943  6-OH  H   (CH 2) 5Ph     H      H    1-AI-Pip(4) 944  H     H   (CH 2) 6Ph     H      H    1-AI-Pip(4) 945  6-OH  H   (CH 2) 6Ph     H      H    1-AI-Pip(4) 946  H     H   CHO            H      H    1-AI-Pip(4) 947  6-OH  H   CHO            H      H    1-AI-Pip(4) 948  H     H   Ac             H      H    1-AI-Pip(4) 949  H     H   Ac             2-F    H    1-AI-Pip(4) 950  H     H   Ac             3-F    H    1-AI-Pip(4) 951  H     H   Ac             2-Cl   H    1-AI-Pip(4) 952  H     H   Ac             3-Cl   H    1-AI-Pip(4) 953  H     H   Ac             2-Br   H    1-AI-Pip(4) 954  H     H   Ac             3-Br   H    1-AI-Pip(4) 955  H     H   Ac             2-I    H    1-AI-Pip(4) 956  H     H   Ac             3-I    H    1-AI-Pip(4) 957  H     H   Ac             2-Me   H    1-AI-Pip(4) 958  H     H   Ac             3-Me   H    1-AI-Pip(4) 959  H     H   Ac             2-Et   H    1-AI-Pip(4) 960  H     H   Ac             3-Et   H    1-AI-Pip(4) 961  H     H   Ac             2-Pr   H    1-AI-Pip(4) 962  H     H   Ac             3-Pr   H    1-AI-Pip(4) 963  H     H   Ac             2-Bu   H    1-AI-Pip(4) 964  H    H   Ac    3-Bu       H    1-AI-Pip(4) 965  H    H   Ac    2-Pn       H    1-AI-Pip(4) 966  H    H   Ac    3-Pn       H    1-AI-Pip(4) 967  H    H   Ac    2-Hx       H    1-AI-Pip(4) 968  H    H   Ac    3-Hx       H    1-AI-Pip(4) 969  H    H   Ac    2-CF 3     H    1-AI-Pip(4) 970  H    H   Ac    3-CF 3     H    1-AI-Pip(4) 971  H    H   Ac    2-OMe      H    1-AI-Pip(4) 972  H    H   Ac    3-OMe      H    1-AI-Pip(4) 973  H    H   Ac    2-OEt      H    1-AI-Pip(4) 974  H    H   Ac    3-OEt      H    1-AI-Pip(4) 975  H    H   Ac    2-COOH     H    1-AI-Pip(4) 976  H    H   Ac    3-COOH     H    1-AI-Pip(4) 977  H    H   Ac    2-COOMe    H    1-AI-Pip(4) 978  H    H   Ac    3-COOMe    H    1-AI-Pip(4) 979  H    H   Ac    2-COOEt    H    1-AI-Pip(4) 980  H    H   Ac    3-COOEt    H    1-AI-Pip(4) 981  H    H   Ac    2-COOPr    H    1-AI-Pip(4) 982  H    H   Ac    3-COOPr    H    1-AI-Pip(4) 983  H    H   Ac    2-COOBu    H    1-AI-Pip(4) 984  H    H   Ac    3-COOBu    H    1-AI-Pip(4) 985  H    H   Ac    2-COOPn    H    1-AI-Pip(4) 986  H    H   Ac    3-COOPn    H    1-AI-Pip(4) 987  H    H   Ac    2-COOHx    H    1-AI-Pip(4) 988  H    H   Ac    3-COOHx    H    1-AI-Pip(4) 989  H    H   Ac    2-CONH 2   H    1-AI-Pip(4) 990  H    H   Ac    3-CONH 2   H    1-AI-Pip(4) 991  H    H   Ac    2-CONHMe   H    1-AI-Pip(4) 992  H    H   Ac    3-CONHMe   H    1-AI-Pip(4) 993   H     H   Ac         2-CONHEt    H        1-AI-Pip(4) 994   H     H   Ac         3-CONHEt    H        1-AI-Pip(4) 995   H     H   Ac         2-CON(Me) 2 H        1-AI-Pip(4) 996   H     H   Ac         3-CON(Me) 2 H        1-AI-Pip(4) 997   H     H   Ac         2-CON(Me)Et H        1-AI-Pip(4) 998   H     H   Ac         3-CON(Me)Et H        1-AI-Pip(4) 999   H     H   Ac         2-CON(Et) 2 H        1-AI-Pip(4) 1000  H     H   Ac         3-CON(Et) 2 H        1-AI-Pip(4) 1001  H     H   Ac         3-F         5-F      1-AI-Pip(4) 1002  H     H   Ac         3-Cl        5-Cl     1-AI-Pip(4) 1003  H     H   Ac         3-Me        5-Me     1-AI-Pip(4) 1004  H     H   Ac         3-Cl        5-CONH 2 1-AI-Pip(4) 1005  H     H   Ac         2-Me        5-CONH 2 1-AI-Pip(4) 1006  H     H   Ac         3-Me        5-CONH 2 1-AI-Pip(4) 1007  H     H   Ac         3-CONH 2    5-CONH 2 1-AI-Pip(4) 1008  H     H   Prn        H           H        1-AI-Pip(4) 1009  6-OH  H   Prn        H           H        1-AI-Pip(4) 1010  H     H   Byr        H           H        1-AI-Pip(4) 1011  6-OH  H   Byr        H           H        1-AI-Pip(4) 1012  H     H   Va         H           H        1-AI-Pip(4) 1013  6-OH  H   Va         H           H        1-AI-Pip(4) 1014  H     H   COCH 2OH   H           H        1-AI-Pip(4) 1015  H     H   COCH 2OH   2-F         H        1-AI-Pip(4) 1016  H     H   COCH 2OH   3-F         H        1-AI-Pip(4) 1017  H     H   COCH 2OH   2-Cl        H        1-AI-Pip(4) 1018  H     H   COCH 2OH   3-Cl        H        1-AI-Pip(4) 1O19  H     H   COCH 2OH   2-Br        H        1-AI-Pip(4) 1020  H     H   COCH 2OH   3-Br        H        1-AI-Pip(4) 1021  H     H   COCH 2OH   2-I         H        1-AI-Pip(4) 1022  H    H  COCH 2OH    3-I        H     1-AI-Pip(4) 1023  H    H  COCH 2OH    2-Me       H     1-AI-Pip(4) 1024  H    H  COCH 2OH    3-Me       H     1-AI-Pip(4) 1025  H    H  COCH 2OH    2-Et       H     1-AI-Pip(4) 1026  H    H  COCH 2OH    3-Et       H     1-AI-Pip(4) 1027  H    H  COCH 2OH    2-Pr       H     1-AI-Pip(4) 1028  H    H  COCH 2OH    3-Pr       H     1-AI-Pip(4) 1029  H    H  COCH 2OH    2-Bu       H     1-AI-Pip(4) 1030  H    H  COCH 2OH    3-Bu       H     1-AI-Pip(4) 1031  H    H  COCH 2OH    2-Pn       H     1-AI-Pip(4) 1032  H    H  COCH 2OH    3-Pn       H     1-AI-Pip(4) 1033  H    H  COCH 2OH    2-Hx       H     1-AI-Pip(4) 1034  H    H  COCH 2OH    3-Hx       H     1-AI-Pip(4) 1035  H    H  COCH 2OH    2-CF 3     H     1-AI-Pip(4) 1036  H    H  COCH 2OH    3-CF 3     H     1-AI-Pip(4) 1037  H    H  COCH 2OH    2-OMe      H     1-AI-Pip(4) 1038  H    H  COCH 2OH    3-OMe      H     1-AI-Pip(4) 1039  H    H  COCH 2OH    2-OEt      H     1-AI-Pip(4) 1040  H    H  COCH 2OH    3-OEt      H     1-AI-Pip(4) 1041  H    H  COCH 2OH    2-COOH     H     1-AI-Pip(4) 1042  H    H  COCH 2OH    3-COOH     H     1-AI-Pip(4) 1043  H    H  COCH 2OH    2-COOMe    H     1-AI-Pip(4) 1044  H    H  COCH 2OH    3-COOMe    H     1-AI-Pip(4) 1045  H    H  COCH 2OH    2-COOEt    H     1-AI-Pip(4) 1046  H    H  COCH 2OH    3-COOEt    H     1-AI-Pip(4) 1047  H    H  COCH 2OH    2-COOPr    H     1-AI-Pip(4) 1048  H    H  COCH 2OH    3-COOPr    H     1-AI-Pip(4) 1049  H    H  COCH 2OH    2-COOBu    H     1-AI-Pip(4) 1050  H    H  COCH 2OH    3-COOBu    H     1-AI-Pip(4) 1051  H    H  COCH 2OH      2-COOPn       H          1-AI-Pip(4) 1052  H    H  COCH 2OH      3-COOPn       H          1-AI-Pip(4) 1053  H    H  COCH 2OH      2-COOHx       H          1-AI-Pip(4) 1054  H    H  COCH 2OH      3-COOHx       H          1-AI-Pip(4) 1055  H    H  COCH 2OH      2-CONH 2      H          1-AI-Pip(4) 1056  H    H  COCH 2OH      3-CONH 2      H          1-AI-Pip(4) 1057  H    H  COCH 2OH      2-CONHMe      H          1-AI-Pip(4) 1058  H    H  COCH 2OH      3-CONHMe      H          1-AI-Pip(4) 1059  H    H  COCH 2OH      2-CONHEt      H          1-AI-Pip(4) 1060  H    H  COCH 2OH      3-CONHEt      H          1-AI-Pip(4) 1061  H    H  COCH 2OH      2-CON(Me) 2   H          1-AI-Pip(4) 1062  H    H  COCH 2OH      3-CON(Me) 2   H          1-AI-Pip(4) 1063  H    H  COCH 2OH      2-CON(Me)Et   H          1-AI-Pip(4) 1064  H    H  COCH 2OH      3-CON(Me)Et   H          1-AI-Pip(4) 1065  H    H  COCH 2OH      2-CON(Et) 2   H          1-AI-Pip(4) 1066  H    H  COCH 2OH      3-CON(Et) 2   H          1-AI-Pip(4) 1067  H    H  COCH 2OH      3-F           5-F        1-AI-Pip(4) 1068  H    H  COCH 2OH      3-Cl          5-Cl       1-AI-Pip(4) 1069  H    H  COCH 2OH      3-Me          5-Me       1-AI-Pip(4) 1070  H    H  COCH 2OH      3-Cl          5-CONH 2   1-AI-Pip(4) 1071  H    H  COCH 2OH      2-Me          5-CONH 2   1-AI-Pip(4) 1072  H    H  COCH 2OH      3-Me          5-CONH 2   1-AI-Pip(4) 1073  H    H  COCH 2OH      3-CONH 2      5-CONH 2   1-AI-Pip(4) 1074  H    H  CO(CH 2) 2OH  H             H          1-AI-Pip(4) 1075  H    H  CO(CH 2) 3OH  H             H          1-AI-Pip(4) 1076  H    H  CO(CH 2) 4OH  H             H          1-AI-Pip(4) 1077  H    H  CO(CH 2) 5OH  H             H          1-AI-Pip(4) 1078  H    H  SO 2Me        H             H          1-AI-Pip(4) 1079  6-OH H  SO 2Me        H             H          1-AI-Pip(4) 1080 H    H  SO 2Et    H        H    1-AI-Pip(4) 1081 H    H  SO 2Et    2-F      H    1-AI-Pip(4) 1082 H    H  SO 2Et    3-F      H    1-AI-Pip(4) 1083 H    H  SO 2Et    2-CL     H    1-AI-Pip(4) 1084 H    H  SO 2Et    3-CL     H    1-AI-Pip(4)  1085 H    H  SO 2Et    2-Br     H    1-AI-Pip(4) 1086 H    H  SO 2Et    3-Br     H    1-AI-Pip(4) 1087 H    H  SO 2Et    2-I      H    1-AI-Pip(4) 1088 H    H  SO 2Et    3-I      H    1-AI-Pip(4) 1089 H    H  SO 2Et    2-Me     H    1-AI-Pip(4) 1090 H    H  SO 2Et    3-Me     H    1-AI-Pip(4) 1091 H    H  SO 2Et    2-Et     H    1-AI-Pip(4) 1092 H    H  SO 2Et    3-Et     H    1-AI-Pip(4) 1093 H    H  SO 2Et    2-Pr     H    1-AI-Pip(4) 1094 H    H  SO 2Et    3-Pr     H    1-AI-Pip(4) 1095 H    H  SO 2Et    2-Bu     H    1-AI-Pip(4) 1096 H    H  SO 2Et    3-Bu     H    1-AI-Pip(4) 1097 H    H  SO 2Et    2-Pn     H    1-AI-Pip(4) 1098 H    H  SO 2Et    3-Pn     H    1-AI-Pip(4) 1099 H    H  SO 2Et    2-Hx     H    1-AI-Pip(4) 1100 H    H  SO 2Et    3-Hx     H    1-AI-Pip(4) 1101 H    H  SO 2Et    2-CF 3   H    1-AI-Pip(4) 1102 H    H  SO 2Et    3-CF 3   H    1-AI-Pip(4) 1103 H    H  SO 2Et    2-OMe    H    1-AI-Pip(4) 1104 H    H  SO 2Et    3-OMe    H    1-AI-Pip(4) 1105 H    H  SO 2Et    2-OEt    H    1-AI-Pip(4) 1106 H    H  SO 2Et    3-OEt    H    1-AI-Pip(4) 1107 H    H  SO 2Et    2-COOH   H    1-AI-Pip(4) 1108 H    H  SO 2Et    3-COOH   H    1-AI-Pip(4) 1109  H    H  SO 2Et    2-COOMe       H    1-AI-Pip(4) 1110  H    H  SO 2Et    3-COOMe       H    1-AI-Pip(4) 1111  H    H  SO 2Et    2-COOEt       H    1-AI-Pip(4) 1112  H    H  SO 2Et    3-COOEt       H    1-AI-Pip(4) 1113  H    H  SO 2Et    2-COOPr       H    1-AI-Pip(4) 1114  H    H  SO 2Et    3-COOPr       H    1-AI-Pip(4) 1115  H    H  SO 2Et    2-COOBu       H    1-AI-Pip(4) 1116  H    H  SO 2Et    3-COOBu       H    1-AI-Pip(4) 1117  H    H  SO 2Et    2-COOPn       H    1-AI-Pip(4) 1118  H    H  SO 2Et    3-COOPn       H    1-AI-Pip(4) 1119  H    H  SO 2Et    2-COOHx       H    1-AI-Pip(4) 1120  H    H  SO 2Et    3-COOHx       H    1-AI-Pip(4) 1121  H    H  SO 2Et    2-CONH 2      H    1-AI-Pip(4) 1122  H    H  SO 2Et    3-CONH 2      H    1-AI-Pip(4) 1123  H    H  SO 2Et    2-CONHMe      H    1-AI-Pip(4) 1124  H    H  SO 2Et    3-CONHMe      H    1-AI-Pip(4) 1125  H    H  SO 2Et    2-CONHEt      H    1-AI-Pip(4) 1126  H    H  SO 2Et    3-CONHEt      H    1-AI-Pip(4) 1127  H    H  SO 2Et    3-CONHPr      H    1-AI-Pip(4) 1128  H    H  SO 2Et    3-CONHBu      H    1-AI-Pip(4) 1129  H    H  SO 2Et    3-CONHPn      H    1-AI-Pip(4) 1130  H    H  SO 2Et    3-CONHHx      H    1-AI-Pip(4) 1131  H    H  SO 2Et    2-CON(Me) 2   H    1-AI-Pip(4) 1132  H    H  SO 2Et    3-CON(Me) 2   H    1-AI-Pip(4) 1133  H    H  SO 2Et    2-ON(Me)Et    H    1-AI-Pip(4) 1134  H    H  SO 2Et    3-CON(Me)Et   H    1-AI-Pip(4) 1135  H    H  SO 2Et    2-CON(Et) 2   H    1-AI-Pip(4) 1136  H    H  SO 2Et    3-CON(Et) 2   H    1-AI-Pip(4) 1137  H    H  SO 2Et    3-CON(Pr) 2   H    1-AI-Pip(4) 1138  H    H  SO 2Et    3-CON(Bu) 2   H          1-AI-Pip(4) 1139  H    H  SO 2Et    3-CON(Pn) 2   H          1-AI-Pip(4) 1140  H    H  SO 2Et    3-CON(Hx) 2   H          1-AI-Pip(4) 1141  H    H  SO 2Et    2-F           3-F        1-AI-Pip(4) 1142  H    H  SO 2Et    2-F           5-F        1-AI-Pip(4) 1143  H    H  SO 2Et    2-F           6-F        1-AI-Pip(4) 1144  H    H  SO 2Et    3-F           5-F        1-AI-Pip(4) 1145  H    H  SO 2Et    2-Cl          3-Cl       1-AI-Pip(4) 1146  H    H  SO 2Et    2-Cl          5-Cl       1-AI-Pip(4) 1147  H    H  SO 2Et    2-Cl          5-Cl       1-AI-Pip(4) 1148  H    H  SO 2Et    3-Cl          5-Cl       1-AI-Pip(4) 1149  H    H  SO 2Et    2-Me          3-Me       1-AI-Pip(4) 1150  H    H  SO 2Et    2-Me          5-Me       1-AI-Pip(4) 1151  H    H  SO 2Et    2-Me          5-Me       1-AI-Pip(4) 1152  H    H  SO 2Et    3-Me          5-Me       1-AI-Pip(4) 1153  H    H  SO 2Et    2-Cl          5-CONH 2   1-AI-Pip(4) 1154  H    H  SO 2Et    2-Cl          5-CONH 2   1-AI-Pip(4) 1155  H    H  SO 2Et    3-Cl          5-CONH 2   1-AI-Pip(4) 1156  H    H  SO 2Et    2-Me          5-CONH 2   1-AI-Pip(4) 1157  H    H  SO 2Et    3-Me          5-CONH 2   1-AI-Pip(4) 1158  H    H  SO 2Et    2-CONH 2      5-CONH 2   1-AI-Pip(4) 1159  H    H  SO 2Et    3-CONH 2      5-CONH 2   1-AI-Pip(4) 1160  H    F  SO 2Et    H             H          1-AI-Pip(4) 1161  H    F  SO 2Et    2-F           H          1-AI-Pip(4) 1162  H    F  SO 2Et    3-F           H          1-AI-Pip(4) 1163  H    F  SO 2Et    2-Cl          H          1-AI-Pip(4) 1164  H    F  SO 2Et    3-Cl          H          1-AI-Pip(4) 1165  H    F  SO 2Et    2-Br          H          1-AI-Pip(4) 1166  H    F  SO 2Et    3-Br          H          1-AI-Pip(4) 1167  H    F  SO 2Et    2-I        H    1-AI-Pip(4) 1168  H    F  SO 2Et    3-I        H    1-AI-Pip(4) 1169  H    F  SO 2Et    2-Me       H    1-AI-Pip(4) 1170  H    F  SO 2Et    3-Me       H    1-AI-Pip(4) 1171  H    F  SO 2Et    2-Et       H    1-AI-Pip(4) 1172  H    F  SO 2Et    3-Et       H    1-AI-Pip(4) 1173  H    F  SO 2Et    2-Pr       H    1-AI-Pip(4) 1174  H    F  SO 2Et    3-Pr       H    1-AI-Pip(4) 1175  H    F  SO 2Et    2-Bu       H    1-AI-Pip(4) 1176  H    F  SO 2Et    3-Bu       H    1-AI-Pip(4) 1177  H    F  SO 2Et    2-Pn       H    1-AI-Pip(4) 1178  H    F  SO 2Et    3-Pn       H    1-AI-Pip(4) 1179  H    F  SO 2Et    2-Hx       H    1-AI-Pip(4) 1180  H    F  SO 2Et    3-Hx       H    1-AI-Pip(4) 1181  H    F  SO 2Et    2-CF 3     H    1-AI-Pip(4) 1182  H    F  SO 2Et    3-CF 3     H    1-AI-Pip(4) 1183  H    F  SO 2Et    2-OMe      H    1-AI-Pip(4) 1184  H    F  SO 2Et    2-OMe      H    1-AI-Pip(4) 1185  H    F  SO 2Et    2-OEt      H    1-AI-Pip(4) 1186  H    F  SO 2Et    3-OEt      H    1-AI-Pip(4) 1187  H    F  SO 2Et    2-COOH     H    1-AI-Pip(4) 1188  H    F  SO 2Et    3-COOH     H    1-AI-Pip(4) 1189  H    F  SO 2Et    2-COOMe    H    1-AI-Pip(4) 1190  H    F  SO 2Et    3-COOMe    H    1-AI-Pip(4) 1191  H    F  SO 2Et    2-COOEt    H    1-AI-Pip(4) 1192  H    F  SO 2Et    3-COOEt    H    1-AI-Pip(4) 1193  H    F  SO 2Et    2-COOPr    H    1-AI-Pip(4) 1194  H    F  SO 2Et    3-COOPr    H    1-AI-Pip(4) 1195  H    F  SO 2Et    2-COOBu    H    1-AI-Pip(4) 1196  H    F   SO 2Et    3-COOBu     H         1-AI-Pip(4) 1197  H    F   SO 2Et    2-COOPn     H         1-AI-Pip(4) 1198  H    F   SO 2Et    3-COOPn     H         1-AI-Pip(4) 1199  H    F   SO 2Et    2-COOHx     H         1-AI-Pip(4) 1200  H    F   SO 2Et    3-COOHx     H         1-AI-Pip(4) 1201  H    F   SO 2Et    2-CONH 2    H         1-AI-Pip(4) 1202  H    F   SO 2Et    3-CONH 2    H         1-AI-Pip(4) 1203  H    F   SO 2Et    2-ONHMe     H         1-AI-Pip(4) 1204  H    F   SO 2Et    3-CONHMe    H         1-AI-Pip(4) 1205  H    F   SO 2Et    2-CONHEt    H         1-AI-Pip(4) 1206  H    F   SO 2Et    3-CONHEt    H         1-AI-Pip(4) 1207  H    F   SO 2Et    2-CON(Me) 2 H         1-AI-Pip(4) 1208  H    F   SO 2Et    3-CON(Me) 2 H         1-AI-Pip(4) 1209  H    F   SO 2Et    2-CON(Me)ET H         1-AI-Pip(4) 1210  H    F   SO 2Et    3-CON(Me)Et H         1-AI-Pip(4) 1211  H    F   SO 2Et    2-CON(Et) 2 H         1-AI-Pip(4) 1212  H    F   SO 2Et    3-CON(Et) 2 H         1-AI-Pip(4) 1213  H    F   SO 2Et    3-F         5-F       1-AI-Pip(4) 1214  H    F   SO 2Et    3-Cl        5-Cl      1-AI-Pip(4) 1215  H    F   SO 2Et    3-Me        5-Me      1-AI-Pip(4) 1216  H    F   SO 2Et    3-Cl        5-CONH 2  1-AI-Pip(4) 1217  H    F   SO 2Et    2-Me        5-CONH 2  1-AI-Pip(4) 1218  H    F   SO 2Et    3-Me        5-CONH 2  1-AI-Pip(4) 1219  H    F   SO 2Et    3-CONH 2    5-CONH 2  1-AI-Pip(4) 1220  H    Me  SO 2Et    H           H         1-AI-Pip(4) 1221  H    Me  SO 2Et    2-F         H         1-AI-Pip(4) 1222  H    Me  SO 2Et    3-F         H         1-AI-Pip(4) 1223  H    Me  SO 2Et    2-Cl        H         1-AI-Pip(4) 1224  H    Me  SO 2Et    3-Cl        H         1-AI-Pip(4) 1225  H    Me  SO 2Et    2-Br      H    1-AI-Pip(4) 1226  H    Me  SO 2Et    3-Br      H    1-AI-Pip(4) 1227  H    Me  SO 2Et    2-I       H    1-AI-Pip(4) 1228  H    Me  SO 2Et    3-I       H    1-AI-Pip(4) 1229  H    Me  SO 2Et    2-Me      H    1-AI-Pip(4) 1230  H    Me  SO 2Et    3-Me      H    1-AI-Pip(4) 1231  H    Me  SO 2Et    2-Et      H    1-AI-Pip(4) 1232  H    Me  SO 2Et    3-Et      H    1-AI-Pip(4) 1233  H    Me  SO 2Et    2-Pr      H    1-AI-Pip(4) 1234  H    Me  SO 2Et    3-Pr      H    1-AI-Pip(4) 1235  H    Me  SO 2Et    2-Bu      H    1-AI-Pip(4) 1236  H    Me  SO 2Et    3-Bu      H    1-AI-Pip(4) 1237  H    Me  SO 2Et    2-Pn      H    1-AI-Pip(4) 1238  H    Me  SO 2Et    3-Pn      H    1-AI-Pip(4) 1239  H    Me  SO 2Et    2-Hx      H    1-AI-Pip(4) 1240  H    Me  SO 2Et    3-Hx      H    1-AI-Pip(4) 1241  H    Me  SO 2Et    2-CF 3    H    1-AI-Pip(4) 1242  H    Me  SO 2Et    3-CF 3    H    1-AI-Pip(4) 1243  H    Me  SO 2Et    2-OMe     H    1-AI-Pip(4) 1244  H    Me  SO 2Et    3-OMe     H    1-AI-Pip(4) 1245  H    Me  SO 2Et    2-OEt     H    1-AI-Pip(4) 1246  H    Me  SO 2Et    3-OEt     H    1-AI-Pip(4) 1247  H    Me  SO 2Et    2-COOH    H    1-AI-Pip(4) 1248  H    Me  SO 2Et    3-COOH    H    1-AI-Pip(4) 1249  H    Me  SO 2Et    2-COOMe   H    1-AI-Pip(4) 1250  H    Me  SO 2Et    3-COOMe   H    1-AI-Pip(4) 12S1  H    Me  SO 2Et    2-COOEt   H    1-AI-Pip(4) 1252  H    Me  SO 2Et    3-COOEt   H    1-AI-Pip(4) 1253  H    Me  SO 2Et    2-COOPr   H    1-AI-Pip(4) 1254  H    Me  SO 2Et    3-COOPr      H          1-AI-Pip(4) 1255  H    Me  SO 2Et    2-COOBu      H          1-AI-Pip(4) 1256  H    Me  SO 2Et    3-COOBu      H          1-AI-Pip(4) 1257  H    Me  SO 2Et    2-COOPn      H          1-AI-Pip(4) 1258  H    Me  SO 2Et    3-COOPn      H          1-AI-Pip(4) 1259  H    Me  SO 2Et    2-COOHx      H          1-AI-Pip(4) 1260  H    Me  SO 2Et    3-COOHx      H          1-AI-Pip(4) 1261  H    Me  SO 2Et    2-CONH 2     H          1-AI-Pip(4) 1262  H    Me  SO 2Et    3-CONH 2     H          1-AI-Pip(4) 1263  H    Me  SO 2Et    2-CONHMe     H          1-AI-Pip(4) 1264  H    Me  SO 2Et    3-CONHMe     H          1-AI-Pip(4) 1265  H    Me  SO 2Et    2-CONHEt     H          1-AI-Pip(4) 1266  H    Me  SO 2Et    3-CONHEt     H          1-AI-Pip(4) 1267  H    Me  SO 2Et    2-CON(Me) 2  H          1-AI-Pip(4) 1268  H    Me  SO 2Et    3-CON(Me) 2  H          1-AI-Pip(4) 1269  H    Me  SO 2Et    2-CON(Me)Et  H          1-AI-Pip(4) 1270  H    Me  SO 2Et    3-CON(Me)Et  H          1-AI-Pip(4) 1271  H    Me  SO 2Et    2-CON(Et) 2  H          1-AI-Pip(4) 1272  H    Me  SO 2Et    3-CON(Et) 2  H          1-AI-Pip(4) 1273  H    Me  SO 2Et    3-F          5-F        1-AI-Pip(4) 1274  H    Me  SO 2Et    3-Cl         5-Cl       1-AI-Pip(4) 1275  H    Me  SO 2Et    3-Me         5-Me       1-AI-Pip(4) 1276  H    Me  SO 2Et    3-Cl         5-CONH 2   1-AI-Pip(4) 1277  H    Me  SO 2Et    2-Me         5-CONH 2   1-AI-Pip(4) 1278  H    Me  SO 2Et    3-Me         5-CONH 2   1-AI-Pip(4) 1279  H    Me  SO 2Et    3-CONH 2     5-CONH 2   1-AI-Pip(4) 1280  6-F  H   SO 2Et    H            H          1-AI-Pip(4) 1281  6-F  H   SO 2Et    2-F          H          1-AI-Pip(4) 1282  6-F  H   SO 2Et    3-F          H          1-AI-Pip(4) 1283  6-F    H  SO 2Et    2-Cl      H    1-AI-Pip(4) 1284  6-F    H  SO 2Et    3-Cl      H    1-AI-Pip(4) 1285  6-F    H  SO 2Et    2-Br      H    1-AI-Pip(4) 1286  6-F    H  SO 2Et    3-Br      H    1-AI-Pip(4) 1287  6-F    H  SO 2Et    2-I       H    1-AI-Pip(4) 1288  6-F    H  SO 2Et    3-I       H    1-AI-Pip(4) 1289  6-F    H  SO 2Et    2-Me      H    1-AI-Pip(4) 1290  6-F    H  SO 2Et    3-Me      H    1-AI-Pip(4) 1291  6-F    H  SO 2Et    2-Et      H    1-AI-Pip(4) 1292  6-F    H  SO 2Et    3-Et      H    1-AI-Pip(4) 1293  6-F    H  SO 2Et    2-Pr      H    1-AI-Pip(4) 1294  6-F    H  SO 2Et    3-Pr      H    1-AI-Pip(4) 1295  6-F    H  SO 2Et    2-Bu      H    1-AI-Pip(4) 1296  6-F    H  SO 2Et    3-Bu      H    1-AI-Pip(4) 1297  6-F    H  SO 2Et    2-Pn      H    1-AI-Pip(4) 1298  6-F    H  SO 2Et    3-Pn      H    1-AI-Pip(4) 1299  6-F    H  SO 2Et    2-Hx      H    1-AI-Pip(4) 1300  6-F    H  SO 2Et    3-Hx      H    1-AI-Pip(4) 1301  6-F    H  SO 2Et    2-CF 3    H    1-AI-Pip(4) 1302  6-F    H  SO 2Et    3-CF 3    H    1-AI-Pip(4) 1303  6-F    H  SO 2Et    2-OMe     H    1-AI-Pip(4) 1304  6-F    H  SO 2Et    3-OMe     H    1-AI-Pip(4) 1305  6-F    H  SO 2Et    2-OEt     H    1-AI-Pip(4) 1306  6-F    H  SO 2Et    3-OEt     H    1-AI-Pip(4) 1307  6-F    H  SO 2Et    2-COOH    H    1-AI-Pip(4) 1308  6-F    H  SO 2Et    3-COOH    H    1-AI-Pip(4) 1309  6-F    H  SO 2Et    2-COOMe   H    1-AI-Pip(4) 1310  6-F    H  SO 2Et    3-COOMe   H    1-AI-Pip(4) 1311  6-F    H  SO 2Et    2-COOEt   H    1-AI-Pip(4) 1312  6-F    H  SO 2Et    3-COOEt       H        1-AI-Pip(4) 1313  6-F    H  SO 2Et    2-COOPr       H        1-AI-Pip(4) 1314  6-F    H  SO 2Et    3-COOPr       H        1-AI-Pip(4) 1315  6-F    H  SO 2Et    2-COOBu       H        1-AI-Pip(4) 1316  6-F    H  SO 2Et    3-COOBu       H        1-AI-Pip(4) 1317  6-F    H  SO 2Et    2-COOPn       H        1-AI-Pip(4) 1318  6-F    H  SO 2Et    3-COOPn       H        1-AI-Pip(4) 1319  6-F    H  SO 2Et    2-COOHx       H        1-AI-Pip(4) 1320  6-F    H  SO 2Et    3-COOHx       H        1-AI-Pip(4) 1321  6-F    H  SO 2Et    2-CONH 2      H        1-AI-Pip(4) 1322  6-F    H  SO 2Et    3-CONH 2      H        1-AI-Pip(4) 1323  6-F    H  SO 2Et    2-CONHMe      H        1-AI-Pip(4) 1324  6-F    H  SO 2Et    3-CONHMe      H        1-AI-Pip(4) 1325  6-F    H  SO 2Et    2-CONHEt      H        1-AI-Pip(4) 1326  6-F    H  SO 2Et    3-CONHEt      H        1-AI-Pip(4) 1327  6-F    H  SO 2Et    2-CON(Me) 2   H        1-AI-Pip(4) 1328  6-F    H  SO 2Et    3-CON(Me) 2   H        1-AI-Pip(4) 1329  6-F    H  SO 2Et    2-CON(Me)Et   H        1-AI-Pip(4) 1330  6-F    H  SO 2Et    3-CON(Me)Et   H        1-AI-Pip(4) 1331  6-F    H  SO 2Et    2-CON(Et) 2   H        1-AI-Pip(4) 1332  6-F    H  SO 2Et    3-CON(Et) 2   H        1-AI-Pip(4) 1333  6-F    H  SO 2Et    3-F           5-F      1-AI-Pip(4) 1334  6-F    H  SO 2Et    3-Cl          5-Cl     1-AI-Pip(4) 1335  6-F    H  SO 2Et    3-Me          5-Me     1-AI-Pip(4) 1336  6-F    H  SO 2Et    3-Cl          5-CONH 2 1-AI-Pip(4) 1337  6-F    H  SO 2Et    2-Me          5-CONH 2 1-AI-Pip(4) 1338  6-F    H  SO 2Et    3-Me          5-CONH 2 1-AI-Pip(4) 1339  6-F    H  SO 2Et    3-CONH 2      5-CONH 2 1-AI-Pip(4) 1340  6-OH   H  SO 2Et    H             H        1-AI-Pip(4) 1341  6-OH  H  SO 2Et    2-F         H    1-AI-Pip(4) 1342  6-OH  H  SO 2Et    3-F         H    1-AI-Pip(4) 1343  6-OH  H  SO 2Et    2-Cl        H    1-AI-Pip(4) 1344  6-OH  H  SO 2Et    3-Cl        H    1-AI-Pip(4) 1345  6-OH  H  SO 2Et    2-Br        H    1-AI-Pip(4) 1346  6-OH  H  SO 2Et    3-Br        H    1-AI-Pip(4) 1347  6-OH  H  SO 2Et    2-I         H    1-AI-Pip(4) 1348  6-OH  H  SO 2Et    3-I         H    1-AI-Pip(4) 1349  6-OH  H  SO 2Et    2-Me        H    1-AI-Pip(4) 1350  6-OH  H  SO 2Et    3-Me        H    1-AI-Pip(4) 1351  6-OH  H  SO 2Et    2-Et        H    1-AI-Pip(4) 1352  6-OH  H  SO 2Et    3-Et        H    1-AI-Pip(4) 1353  6-OH  H  SO 2Et    2-Pr        H    1-AI-Pip(4) 1354  6-OH  H  SO 2Et    3-Pr        H    1-AI-Pip(4) 1355  6-OH  H  SO 2Et    2-Bu        H    1-AI-Pip(4) 1356  6-OH  H  SO 2Et    3-Bu        H    1-AI-Pip(4) 1357  6-OH  H  SO 2Et    2-Pn        H    1-AI-Pip(4) 1358  6-OH  H  SO 2Et    3-Pn        H    1-AI-Pip(4) 1359  6-OH  H  SO 2Et    2-Hx        H    1-AI-Pip(4) 1360  6-OH  H  SO 2Et    3-Hx        H    1-AI-Pip(4) 1361  6-OH  H  SO 2Et    2-CF 3      H    1-AI-Pip(4) 1362  6-OH  H  SO 2Et    3-CF 3      H    1-AI-Pip(4) 1363  6-OH  H  SO 2Et    2-OMe       H    1-AI-Pip(4) 1364  6-OH  H  SO 2Et    3-OMe       H    1-AI-Pip(4) 1365  6-OH  H  SO 2Et    2-OEt       H    1-AI-Pip(4) 1366  6-OH  H  SO 2Et    3-OEt       H    1-AI-Pip(4) 1367  6-OH  H  SO 2Et    2-COOH      H    1-AI-Pip(4) 1368  6-OH  H  SO 2Et    3-COOH      H    1-AI-Pip(4) 1369  6-OH  H  SO 2Et    2-COOMe     H    1-AI-Pip(4) 1370  6-OH  H  SO 2Et    3-COOMe        H           1-AI-Pip(4) 1371  6-OH  H  SO 2Et    2-COOEt        H           1-AI-Pip(4) 1372  6-OH  H  SO 2Et    3-COOEt        H           1-AI-Pip(4) 1373  6-OH  H  SO 2Et    2-COOPr        H           1-AI-Pip(4) 1374  6-OH  H  SO 2Et    3-COOPr        H           1-AI-Pip(4) 1375  6-OH  H  SO 2Et    2-COOBu        H           1-AI-Pip(4) 1376  6-OH  H  SO 2Et    3-COOBu        H           1-AI-Pip(4) 1377  6-OH  H  SO 2Et    2-COOPn        H           1-AI-Pip(4) 1378  6-OH  H  SO 2Et    3-COOPn        H           1-AI-Pip(4) 1379  6-OH  H  SO 2Et    2-COOHx        H           1-AI-Pip(4) 1380  6-OH  H  SO 2Et    3-COOHx        H           1-AI-Pip(4) 1381  6-OH  H  SO 2Et    2-CONH 2       H           1-AI-Pip(4) 1382  6-OH  H  SO 2Et    3-CONH 2       H           1-AI-Pip(4) 1383  6-OH  H  SO 2Et    2-CONHMe       H           1-AI-Pip(4) 1384  6-OH  H  SO 2Et    3-CONHMe       H           1-AI-Pip(4) 1385  6-OH  H  SO 2Et    2-CONHEt       H           1-AI-Pip(4) 1386  6-OH  H  SO 2Et    3-CONHEt       H           1-AI-Pip(4) 1387  6-OH  H  SO 2Et    2-CON(Me) 2    H           1-AI-Pip(4) 1388  6-OH  H  SO 2Et    3-CON(Me) 2    H           1-AI-Pip(4) 1389  6-OH  H  SO 2Et    2-CON(Me)Et    H           1-AI-Pip(4) 1390  6-OH  H  SO 2Et    3-CON(Me)Et    H           1-AI-Pip(4) 1391  6-OH  H  SO 2Et    2-CON(Et) 2    H           1-AI-Pip(4) 1392  6-OH  H  SO 2Et    3-CON(Et) 2    H           1-AI-Pip(4) 1393  6-OH  H  SO 2Et    3-F            5-F         1-AI-Pip(4) 1394  6-OH  H  SO 2Et    3-Cl           5-Cl        1-AI-Pip(4) 1395  6-OH  H  SO 2Et    3-Me           5-Me        1-AI-Pip(4) 1396  6-OH  H  SO 2Et    3-Cl           5-CONH 2    1-AI-Pip(4) 1397  6-OH  H  SO 2Et    2-Me           5-CONH 2    1-AI-Pip(4) 1398  6-OH  H  SO 2Et    3-Me           5-CONH 2    1-AI-Pip(4) 1399  6-OH H  SO 2Et           3-CONH 2  5-CONH 2  1-AI-Pip(4) 1400  H    H  SO 2Pr           H         H         1-AI-Pip(4) 1401  H    H  SO 2iPr          H         H         1-AI-Pip(4) 1402  H    H  SO 2Bu           H         H         1-AI-Pip(4) 1403  H    H  SO 2sBu          H         H         1-AI-Pip(4) 1404  H    H  SO 2iBu          H         H         1-AI-Pip(4) 1405  H    H  SO 2tBu          H         H         1-AI-Pip(4) 1406  H    H  SO 2Pn           H         H         1-AI-Pip(4) 1407  H    H  SO 2Hx           H         H         1-AI-Pip(4) 1408  H    H  SO 2CH 2COOEt    H         H         1-AI-Pip(4) 1409  6-OH H  SO 2CH 2COOMe    H         H         1-AI-Pip(4) 1410  H    H  SO 2CH 2COOEt    H         H         1-AI-Pip(4) 1411  H    H  SO 2CH 2COOEt    2-F       H         1-AI-Pip(4) 1412  H    H  SO 2CH 2COOEt    3-F       H         1-AI-Pip(4) 1413  H    H  SO 2CH 2COOEt    2-Cl      H         1-AI-Pip(4) 1414  H    H  SO 2CH 2COOEt    3-Cl      H         1-AI-Pip(4) 1415  H    H  SO 2CH 2COOEt    2-Br      H         1-AI-Pip(4) 1416  H    H  SO 2CH 2COOEt    3-Br      H         1-AI-Pip(4) 1417  H    H  SO 2CH 2COOEt    2-I       H         1-AI-Pip(4) 1418  H    H  SO 2CH 2COOEt    3-I       H         1-AI-Pip(4) 1419  H    H  SO 2CH 2COOEt    2-Me      H         1-AI-Pip(4) 1420  H    H  SO 2CH 2COOEt    3-Me      H         1-AI-Pip(4) 1421  H    H  SO 2CH 2COOEt    2-Et      H         1-AI-Pip(4) 1422  H    H  SO 2CH 2COOEt    3-Et      H         1-AI-Pip(4) 1423  H    H  SO 2CH 2COOEt    2-Pr      H         1-AI-Pip(4) 1424  H    H  SO 2CH 2COOEt    3-Pr      H         1-AI-Pip(4) 1425  H    H  SO 2CH 2COOEt    2- iPr   H         1-AI-Pip(4) 1426  H    H  SO 2CH 2COOEt    3- iPr   H         1-AI-Pip(4) 1427  H    H  SO 2CH 2COOEt    2-Bu      H         1-AI-Pip(4) 1428  H    H  SO 2CH 2COOEt    3-Bu       H    1-AI-Pip(4) 1429  H    H  SO 2CH 2COOEt    2- iBu    H    1-AI-Pip(4) 1430  H    H  SO 2CH 2COOEt    3- iBu    H    1-AI-Pip(4) 1431  H    H  SO 2CH 2COOEt    2- sBu    H    1-AI-Pip(4) 1432  H    H  SO 2CH 2COOEt    3- sBu    H    1-AI-Pip(4) 1433  H    H  SO 2CH 2COOEt    2- tBu    H    1-AI-Pip(4) 1434  H    H  SO 2CH 2COOEt    3- tBu    H    1-AI-Pip(4) 1435  H    H  SO 2CH 2COOEt    2-Pn       H    1-AI-Pip(4) 1436  H    H  SO 2CH 2COOEt    3-Pn       H    1-AI-Pip(4) 1437  H    H  SO 2CH 2COOEt    2-Hx       H    1-AI-Pip(4) 1438  H    H  SO 2CH 2COOEt    3-Hx       H    1-AI-Pip(4) 1439  H    H  SO 2CH 2COOEt    2-CF 3     H    1-AI-Pip(4) 1440  H    H  SO 2CH 2COOEt    3-CF 3     H    1-AI-Pip(4) 1441  H    H  SO 2CH 2COOEt    2-OMe      H    1-AI-Pip(4) 1442  H    H  SO 2CH 2COOEt    3-OMe      H    1-AI-Pip(4) 1443  H    H  SO 2CH 2COOEt    2-OEt      H    1-AI-Pip(4) 1444  H    H  SO 2CH 2COOEt    3-OEt      H    1-AI-Pip(4) 1445  H    H  SO 2CH 2COOEt    2-COOH     H    1-AI-Pip(4) 1446  H    H  SO 2CH 2COOEt    3-COOH     H    1-AI-Pip(4) 1447  H    H  SO 2CH 2COOEt    2-COOMe    H    1-AI-Pip(4) 1448  H    H  SO 2CH 2COOEt    3-COOMe    H    1-AI-Pip(4) 1449  H    H  SO 2CH 2COOEt    2-COOEt    H    1-AI-Pip(4) 1450  H    H  SO 2CH 2COOEt    3-COOEt    H    1-AI-Pip(4) 1451  H    H  SO 2CH 2COOEt    2-COOPr    H    1-AI-Pip(4) 1452  H    H  SO 2CH 2COOEt    3-COOPr    H    1-AI-Pip(4) 1453  H    H  SO 2CH 2COOEt    2-COOBu    H    1-AI-Pip(4) 1454  H    H  SO 2CH 2COOEt    3-COOBu    H    1-AI-Pip(4) 1455  H    H  SO 2CH 2COOEt    2-COOPn    H    1-AI-Pip(4) 1456  H    H  SO 2CH 2COOEt    3-COOPn    H    1-AI-Pip(4) 1457  H    H  SO 2CH 2COOEt    2-COOHx      H           1-AI-Pip(4) 1458  H    H  SO 2CH 2COOEt    3-COOHx      H           1-AI-Pip(4) 1459  H    H  SO 2CH 2COOEt    2-CONH 2     H           1-AI-Pip(4) 1460  H    H  SO 2CH 2COOEt    3-CONH 2     H           1-AI-Pip(4) 1461  H    H  SO 2CH 2COOEt    2-CONHMe     H           1-AI-Pip(4) 1462  H    H  SO 2CH 2COOEt    3-CONHMe     H           1-AI-Pip(4) 1463  H    H  SO 2CH 2COOEt    2-CONHEt     H           1-AI-Pip(4) 1464  H    H  SO 2CH 2COOEt    3-CONHEt     H           1-AI-Pip(4) 1465  H    H  SO 2CH 2COOEt    2-CON(Me) 2  H           1-AI-Pip(4) 1466  H    H  SO 2CH 2COOEt    3-CON(Me) 2  H           1-AI-Pip(4) 1467  H    H  SO 2CH 2COOEt    2-CON(Me)Et  H           1-AI-Pip(4) 1468  H    H  SO 2CH 2COOEt    3-CON(Me)Et  H           1-AI-Pip(4) 1469  H    H  SO 2CH 2COOEt    2-CON(Et) 2  H           1-AI-Pip(4) 1470  H    H  SO 2CH 2COOEt    3-CON(Et) 2  H           1-AI-Pip(4) 1471  H    H  SO 2CH 2COOEt    2-F          3-F         1-AI-Pip(4) 1472  H    H  SO 2CH 2COOEt    2-F          5-F         1-AI-Pip(4) 1473  H    H  SO 2CH 2COOEt    2-F          6-F         1-AI-Pip(4) 1474  H    H  SO 2CH 2COOEt    3-F          5-F         1-AI-Pip(4) 1475  H    H  SO 2CH 2COOEt    2-Cl         3-Cl        1-AI-Pip(4) 1476  H    H  SO 2CH 2COOEt    2-Cl         5-Cl        1-AI-Pip(4) 1477  H    H  SO 2CH 2COOEt    2-Cl         6-Cl        1-AI-Pip(4) 1478  H    H  SO 2CH 2COOEt    3-Cl         5-Cl        1-AI-Pip(4) 1479  H    H  SO 2CH 2COOEt    2-Me         3-Me        1-AI-Pip(4) 1480  H    H  SO 2CH 2COOEt    2-Me         5-Me        1-AI-Pip(4) 1481  H    H  SO 2CH 2COOEt    2-Me         6-Me        1-AI-Pip(4) 1482  H    H  SO 2CH 2COOEt    3-Me         5-Me        1-AI-Pip(4) 1483  H    H  SO 2CH 2COOEt    2-Cl         5-CONH 2    1-AI-Pip(4) 1484  H    H  SO 2CH 2COOEt    3-Cl         5-CONH 2    1-AI-Pip(4) 1485  H    H  SO 2CH 2COOEt    3-Cl         5-CONHMe    1-AI-Pip(4) 1486  H    H  SO 2CH 2COOEt    3-Cl        5-CONHEt    1-AI-Pip(4) 1487  H    H  SO 2CH 2COOEt    3-Cl        5-CONHPr    1-AI-Pip(4) 1488  H    H  SO 2CH 2COOEt    3-Cl        5-CONHBu    1-AI-Pip(4) 1489  H    H  SO 2CH 2COOEt    3-Cl        5-CONHPn    1-AI-Pip(4) 1490  H    H  SO 2CH 2COOEt    3-Cl        5-CONHHx    1-AI-Pip(4) 1491  H    H  SO 2CH 2COOEt    2-Me        5-CONH 2    1-AI-Pip(4) 1492  H    H  SO 2CH 2COOEt    2-Me        5-CONHMe    1-AI-Pip(4) 1493  H    H  SO 2CH 2COOEt    2-Me        5-CONHEt    1-AI-Pip(4) 1494  H    H  SO 2CH 2COOEt    2-Me        5-CONPr     1-AI-Pip(4) 1495  H    H  SO 2CH 2COOEt    2-Me        5-CONHBu    1-AI-Pip(4) 1496  H    H  SO 2CH 2COOEt    2-Me        5-CONHPn    1-AI-Pip(4) 1497  H    H  SO 2CH 2COOEt    2-Me        5-CONHHx    1-AI-Pip(4) 1498  H    H  SO 2CH 2COOEt    3-Me        5-CONH 2    1-AI-Pip(4) 1499  H    H  SO 2CH 2COOEt    3-Me        5-CONHMe    1-AI-Pip(4) 1500  H    H  SO 2CH 2COOEt    3-Me        5-CONHEt    1-AI-Pip(4) 1501  H    H  SO 2CH 2COOEt    3-Me        5-CONHPr    1-AI-Pip(4) 1502  H    H  SO 2CH 2COOEt    3-Me        5-CONHBu    1-AI-Pip(4) 1503  H    H  SO 2CH 2COOEt    3-Me        5-CONHPn    1-AI-Pip(4) 1504  H    H  SO 2CH 2COOEt    3-Me        5-CONHHx    1-AI-Pip(4) 1505  H    H  SO 2CH 2COOEt    2-CONH 2    6-CONH 2    1-AI-Pip(4) 1506  H    H  SO 2CH 2COOEt    3-CONH 2    5-CONH 2    1-AI-Pip(4) 1507  H    H  SO 2CH 2COOEt    3-CONHMe    5-CONHMe    1-AI-Pip(4) 1508  H    H  SO 2CH 2COOEt    3-CONHEt    5-CONHEt    1-AI-Pip(4) 1509  H    F  SO 2CH 2COOEt    H           H           1-AI-Pip(4) 1510  H    F  SO 2CH 2COOEt    2-F         H           1-AI-Pip(4) 1511  H    F  SO 2CH 2COOEt    3-F         H           1-AI-Pip(4) 1512  H    F  SO 2CH 2COOEt    2-Cl        H           1-AI-Pip(4) 1513  H    F  SO 2CH 2COOEt    3-Cl        H           1-AI-Pip(4) 1514  H    F  SO 2CH 2COOEt    2-Br        H           1-AI-Pip(4) 1515  H    F    SO 2CH 2COOEt    3-Br     H    1-AI-Pip(4) 1516  H    F    SO 2CH 2COOEt    2-I      H    1-AI-Pip(4) 1517  H    F    SO 2CH 2COOEt    3-I      H    1-AI-Pip(4) 1518  H    F    SO 2CH 2COOEt    2-Me     H    1-AI-Pip(4) 1519  H    F    SO 2CH 2COOEt    3-Me     H    1-AI-Pip(4) 1520  H    F    SO 2CH 2COOEt    2-Et     H    1-AI-Pip(4) 1521  H    F    SO 2CH 2COOEt    3-Et     H    1-AI-Pip(4) 1522  H    F    SO 2CH 2COOEt    2-Pr     H    1-AI-Pip(4) 1523  H    F    SO 2CH 2COOEt    3-Pr     H    1-AI-Pip(4) 1524  H    F    SO 2CH 2COOEt    2- iPr  H    1-AI-Pip(4) 1525  H    F    SO 2CH 2COOEt    3- iPr  H    1-AI-Pip(4) 1526  H    F    SO 2CH 2COOEt    2-Bu     H    1-AI-Pip(4) 1527  H    F    SO 2CH 2COOEt    3-Bu     H    1-AI-Pip(4) 1528  H    F    SO 2CH 2COOEt    2- iBu  H    1-AI-Pip(4) 1529  H    F    SO 2CH 2COOEt    3- iBu  H    1-AI-Pip(4) 1530  H    F    SO 2CH 2COOEt    2- sBu  H    1-AI-Pip(4) 1531  H    F    SO 2CH 2COOEt    3- sBu  H    1-AI-Pip(4) 1532  H    F    SO 2CH 2COOEt    2- tBu  H    1-AI-Pip(4) 1533  H    F    SO 2CH 2COOEt    3- tBu  H    1-AI-Pip(4) 1534  H    F    SO 2CH 2COOEt    2-Pn     H    1-AI-Pip(4) 1535  H    F    SO 2CH 2COOEt    3-Pn     H    11-AI-Pip(4) 1536  H    F    SO 2CH 2COOEt    2-Hx     H    1-AI-Pip(4) 1537  H    F    SO 2CH 2COOEt    3-Hx     H    1-AI-Pip(4) 1538  H    F    SO 2CH 2COOEt    2-CF 3   H    1-AI-Pip(4) 1539  H    F    SO 2CH 2COOEt    3-CF 3   H    1-AI-Pip(4) 1540  H    F    SO 2CH 2COOEt    2-OMe    H    1-AI-Pip(4) 1541  H    F    SO 2CH 2COOEt    3-OMe    H    1-AI-Pip(4) 1542  H    F    SO 2CH 2COOEt    2-OEt    H    1-AI-Pip(4) 1543  H    F    SO 2CH 2COOEt    3-OEt    H    1-AI-Pip(4) 1544  H    F  SO 2CH 2COOEt    2-COOH         H       1-AI-Pip(4) 1545  H    F  SO 2CH 2COOEt    3-COOH         H       1-AI-Pip(4) 1546  H    F  SO 2CH 2COOEt    2-COOMe        H       1-AI-Pip(4) 1547  H    F  SO 2CH 2COOEt    3-COOMe        H       1-AI-Pip(4) 1548  H    F  SO 2CH 2COOEt    2-COOEt        H       1-AI-Pip(4) 1549  H    F  SO 2CH 2COOEt    3-COOEt        H       1-AI-Pip(4) 1550  H    F  SO 2CH 2COOEt    2-COOPr        H       1-AI-Pip(4) 1551  H    F  SO 2CH 2COOEt    3-COOPr        H       1-AI-Pip(4) 1552  H    F  SO 2CH 2COOEt    2-COOBu        H       1-AI-Pip(4) 1553  H    F  SO 2CH 2COOEt    3-COOBu        H       1-AI-Pip(4) 1554  H    F  SO 2CH 2COOEt    2-COOPn        H       1-AI-Pip(4) 1555  H    F  SO 2CH 2COOEt    3-COOPn        H       1-AI-Pip(4) 1556  H    F  SO 2CH 2COOEt    2-COOHx        H       1-AI-Pip(4) 1557  H    F  SO 2CH 2COOEt    3-COOHx        H       1-AI-Pip(4) 1558  H    F  SO 2CH 2COOEt    2-CONH 2       H       1-AI-Pip(4) 1559  H    F  SO 2CH 2COOEt    3-CONH 2       H       1-AI-Pip(4) 1560  H    F  SO 2CH 2COOEt    2-CONHMe       H       1-AI-Pip(4) 1561  H    F  SO 2CH 2COOEt    3-CONHMe       H       1-AI-Pip(4) 1562  H    F  SO 2CH 2COOEt    2-CONHEt       H       1-AI-Pip(4) 1563  H    F  SO 2CH 2COOEt    3-CONHEt       H       1-AI-Pip(4) 1564  H    F  SO 2CH 2COOEt    2-CON(Me) 2    H       1-AI-Pip(4) 1565  H    F  SO 2CH 2COOEt    3-CON(Me) 2    H       1-AI-Pip(4) 1566  H    F  SO 2CH 2COOEt    2-CON(Me)Et    H       1-AI-Pip(4) 1567  H    F  SO 2CH 2COOEt    3-CON(Me)Et    H       1-AI-Pip(4) 1568  H    F  SO 2CH 2COOEt    2-CON(Et) 2    H       1-AI-Pip(4) 1569  H    F  SO 2CH 2COOEt    3-CON(Et) 2    H       1-AI-Pip(4) 1570  H    F  SO 2CH 2COOEt    3-F            5-F     1-AI-Pip(4)  1571  H    F  SO 2CH 2COOEt    3-Cl           5-Cl    1-AI-Pip(4) 1572  H    F  SO 2CH 2COOEt    3-Me           5-Me    1-AI-Pip(4) 1573  H    F   SO 2CH 2COOEt    3-Cl     5-CONH 2   1-AI-Pip(4) 1574  H    F   SO 2CH 2COOEt    2-Me     5-CONH 2   1-AI-Pip(4) 1575  H    F   SO 2CH 2COOEt    3-Me     5-CONH 2   1-AI-Pip(4) 1576  H    F   SO 2CH 2COOEt    3-CONH 2 5-CONH 2   1-AI-Pip(4) 1577  H    Me  SO 2CH 2COOEt    H        H          1-AI-Pip(4) 1578  H    Me  SO 2CH 2COOEt    2-F      H          1-AI-Pip(4) 1579  H    Me  SO 2CH 2COOEt    3-F      H          1-AI-Pip(4) 1580  H    Me  SO 2CH 2COOEt    2-Cl     H          1-AI-Pip(4) 1581  H    Me  SO 2CH 2COOEt    3-Cl     H          1-AI-Pip(4) 1582  H    Me  SO 2CH 2COOEt    2-Br     H          1-AI-Pip(4) 1583  H    Me  SO 2CH 2COOEt    3-Br     H          1-AI-Pip(4) 1584  H    Me  SO 2CH 2COOEt    2-I      H          1-AI-Pip(4) 1585  H    Me  SO 2CH 2COOEt    3-I      H          1-AI-Pip(4) 1586  H    Me  SO 2CH 2COOEt    2-Me     H          1-AI-Pip(4) 1587  H    Me  SO 2CH 2COOEt    3-Me     H          1-AI-Pip(4) 1588  H    Me  SO 2CH 2COOEt    2-Et     H          1-AI-Pip(4) 1589  H    Me  SO 2CH 2COOEt    3-Et     H          1-AI-Pip(4) 1590  H    Me  SO 2CH 2COOEt    2-Pr     H          1-AI-Pip(4) 1591  H    Me  SO 2CH 2COOEt    3-Pr     H          1-AI-Pip(4) 1592  H    Me  SO 2CH 2COOEt    2-Bu     H          1-AI-Pip(4) 1593  H    Me  SO 2CH 2COOEt    3-Bu     H          1-AI-Pip(4) 1594  H    Me  SO 2CH 2COOEt    2-Pn     H          1-AI-Pip(4) 1595  H    Me  SO 2CH 2COOEt    3-Pn     H          1-AI-Pip(4) 1596  H    Me  SO 2CH 2COOEt    2-Hx     H          1-AI-Pip(4) 1597  H    Me  SO 2CH 2COOEt    3-Hx     H          1-AI-Pip(4) 1598  H    Me  SO 2CH 2COOEt    2-CF 3   H          1-AI-Pip(4) 1599  H    Me  SO 2CH 2COOEt    3-CF 3   H          1-AI-Pip(4) 1600  H    Me  SO 2CH 2COOEt    2-OMe    H          1-AI-Pip(4) 1601  H    Me  SO 2CH 2COOEt    3-OMe    H          1-AI-Pip(4) 1602  H    Me  SO 2CH 2COOEt    2-OEt          H    1-AI-Pip(4) 1603  H    Me  SO 2CH 2COOEt    3-OEt          H    1-AI-Pip(4) 1604  H    Me  SO 2CH 2COOEt    2-COOH         H    1-AI-Pip(4) 1605  H    Me  SO 2CH 2COOEt    3-COOH         H    1-AI-Pip(4) 1606  H    Me  SO 2CH 2COOEt    2-COOMe        H    1-AI-Pip(4) 1607  H    Me  SO 2CH 2COOEt    3-COOMe        H    1-AI-Pip(4) 1608  H    Me  SO 2CH 2COOEt    2-COOEt        H    1-AI-Pip(4) 1609  H    Me  SO 2CH 2COOEt    3-COOEt        H    1-AI-Pip(4) 1610  H    Me  SO 2CH 2COOEt    2-COOPr        H    1-AI-Pip(4) 1611  H    Me  SO 2CH 2COOEt    3-COOPr        H    1-AI-Pip(4) 1612  H    Me  SO 2CH 2COOEt    2-COOBu        H    1-AI-Pip(4) 1613  H    Me  SO 2CH 2COOEt    3-COOBu        H    1-AI-Pip(4) 1614  H    Me  SO 2CH 2COOEt    2-COOPn        H    1-AI-Pip(4) 1615  H    Me  SO 2CH 2COOEt    3-COOPn        H    1-AI-Pip(4) 1616  H    Me  SO 2CH 2COOEt    2-COOHx        H    1-AI-Pip(4) 1617  H    Me  SO 2CH 2COOEt    3-COOHx        H    1-AI-Pip(4) 1618  H    Me  SO 2CH 2COOEt    2-CONH 2       H    1-AI-Pip(4) 1619  H    Me  SO 2CH 2COOEt    3-CONH 2       H    1-AI-Pip(4) 1620  H    Me  SO 2CH 2COOEt    2-CONHMe       H    1-AI-Pip(4) 1621  H    Me  SO 2CH 2COOEt    3-CONHMe       H    1-AI-Pip(4) 1622  H    Me  SO 2CH 2COOEt    2-CONHEt       H    1-AI-Pip(4) 1623  H    Me  SO 2CH 2COOEt    3-CONHEt       H    1-AI-Pip(4) 1624  H    Me  SO 2CH 2COOEt    2-CON(Me) 2    H    1-AI-Pip(4) 1625  H    Me  SO 2CH 2COOEt    3-CON(Me) 2    H    1-AI-Pip(4) 1626  H    Me  SO 2CH 2COOEt    2-CON(Me)Et    H    1-AI-Pip(4) 1627  H    Me  SO 2CH 2COOEt    3-CON(Me)Et    H    1-AI-Pip(4) 1628  H    Me  SO 2CH 2COOEt    2-CON(Et) 2    H    1-AI-Pip(4) 1629  H    Me  SO 2CH 2COOEt    3-CON(Et) 2    H    1-AI-Pip(4) 1630  H    Me  SO 2CH 2COOEt    3-F            5-F  1-AI-Pip(4) 1631  H      Me  SO 2CH 2COOEt    3-Cl     5-Cl      1-AI-Pip(4) 1632  H      Me  SO 2CH 2COOEt    3-Me     5-Me      1-AI-Pip(4) 1633  H      Me  SO 2CH 2COOEt    3-Cl     5-CONH 2  1-AI-Pip(4) 1634  H      Me  SO 2CH 2COOEt    2-Me     5-CONH 2  1-AI-Pip(4) 1635  H      Me  SO 2CH 2COOEt    3-Me     5-CONH 2  1-AI-Pip(4) 1636  H      Me  SO 2CH 2COOEt    3-CONH 2 5-CONH 2  1-AI-Pip(4) 1637  2-F    H   SO 2CH 2COOEt    H        H         1-AI-Pip(4) 1638  4-F    H   SO 2CH 2COOEt    H        H         1-AI-Pip(4) 1639  4-F    H   SO 2CH 2COOEt    2-F      H         1-AI-Pip(4) 1640  4-F    H   SO 2CH 2COOEt    3-F      H         1-AI-Pip(4) 1641  4-F    H   SO 2CH 2COOEt    2-Cl     H         1-AI-Pip(4) 1642  4-F    H   SO 2CH 2COOEt    3-Cl     H         1-AI-Pip(4) 1643  4-F    H   SO 2CH 2COOEt    2-Br     H         1-AI-Pip(4) 1644  4-F    H   SO 2CH 2COOEt    3-Br     H         1-AI-Pip(4) 1645  4-F    H   SO 2CH 2COOEt    2-I      H         1-AI-Pip(4) 1646  4-F    H   SO 2CH 2COOEt    3-I      H         1-AI-Pip(4) 1647  4-F    H   SO 2CH 2COOEt    2-Me     H         1-AI-Pip(4) 1648  4-F    H   SO 2CH 2COOEt    3-Me     H         1-AI-Pip(4) 1649  4-F    H   SO 2CH 2COOEt    2-Et     H         1-AI-Pip(4) 1650  4-F    H   SO 2CH 2COOEt    3-Et     H         1-AI-Pip(4) 1651  4-F    H   SO 2CH 2COOEt    2-Pr     H         1-AI-Pip(4) 1652  4-F    H   SO 2CH 2COOEt    3-Pr     H         1-AI-Pip(4) 1653  4-F    H   SO 2CH 2COOEt    2-Bu     H         1-AI-Pip(4) 1654  4-F    H   SO 2CH 2COOEt    3-Bu     H         1-AI-Pip(4) 1655  4-F    H   SO 2CH 2COOEt    2-Pn     H         1-AI-Pip(4) 1656  4-F    H   SO 2CH 2COOEt    3-Pn     H         1-AI-Pip(4) 1657  4-F    H   SO 2CH 2COOEt    2-Hx     H         1-AI-Pip(4) 1658  4-F    H   SO 2CH 2COOEt    3-Hx     H         1-AI-Pip(4) 1659  4-F    H   SO 2CH 2COOEt    2-CF 3   H         1-AI-Pip(4) 1660  4-F    H  SO 2CH 2COOEt    3-CF 3        H    1-AI-Pip(4) 1661  4-F    H  SO 2CH 2COOEt    2-OMe         H    1-AI-Pip(4) 1662  4-F    H  SO 2CH 2COOEt    3-OMe         H    1-AI-Pip(4) 1663  4-F    H  SO 2CH 2COOEt    2-OEt         H    1-AI-Pip(4) 1664  4-F    H  SO 2CH 2COOEt    3-OEt         H    1-AI-Pip(4) 1665  4-F    H  SO 2CH 2COOEt    2-COOH        H    1-AI-Pip(4) 1666  4-F    H  SO 2CH 2COOEt    3-COOH        H    1-AI-Pip(4) 1667  4-F    H  SO 2CH 2COOEt    2-COOMe       H    1-AI-Pip(4) 1668  4-F    H  SO 2CH 2COOEt    3-COOMe       H    1-AI-Pip(4) 1669  4-F    H  SO 2CH 2COOEt    2-COOEt       H    1-AI-Pip(4) 1670  4-F    H  SO 2CH 2COOEt    3-COOEt       H    1-AI-Pip(4)  1671  4-F    H  SO 2CH 2COOEt    2-COOPr       H    1-AI-Pip(4) 1672  4-F    H  SO 2CH 2COOEt    3-COOPr       H    1-AI-Pip(4) 1673  4-F    H  SO 2CH 2COOEt    2-COOBu       H    1-AI-Pip(4) 1674  4-F    H  SO 2CH 2COOEt    3-COOBu       H    1-AI-Pip(4) 1675  4-F    H  SO 2CH 2COOEt    2-COOPn       H    1-AI-Pip(4) 1676  4-F    H  SO 2CH 2COOEt    3-COOPn       H    1-AI-Pip(4) 1677  4-F    H  SO 2CH 2COOEt    2-COOHx       H    1-AI-Pip(4) 1678  4-F    H  SO 2CH 2COOEt    3-COOHx       H    1-AI-Pip(4) 1679  4-F    H  SO 2CH 2COOEt    2-CONH 2      H    1-AI-Pip(4) 1680  4-F    H  SO 2CH 2COOEt    3-CONH 2      H    1-AI-Pip(4) 1681  4-F    H  SO 2CH 2COOEt    2-CONHMe      H    1-AI-Pip(4) 1682  4-F    H  SO 2CH 2COOEt    3-CONHMe      H    1-AI-Pip(4) 1683  4-F    H  SO 2CH 2COOEt    2-CONHEt      H    1-AI-Pip(4) 1684  4-F    H  SO 2CH 2COOEt    3-CONHEt      H    1-AI-Pip(4) 1685  4-F    H  SO 2CH 2COOEt    2-CON(Me) 2   H    1-AI-Pip(4) 1686  4-F    H  SO 2CH 2COOEt    3-CON(Me) 2   H    1-AI-Pip(4) 1687  4-F    H  SO 2CH 2COOEt    2-CON(Me)Et   H    1-AI-Pip(4) 1688  4-F    H  SO 2CH 2COOEt    3-CON(Me)Et   H    1-AI-Pip(4) 1689  4-F    H   SO 2CH 2COOEt    2-CON(Et) 2   H        1-AI-Pip(4) 1690  4-F    H   SO 2CH 2COOEt    3-CON(Et) 2   H        1-AI-Pip(4) 1691  4-F    Me  SO 2CH 2COOEt    3-F           5-F      1-AI-Pip(4) 1692  4-F    Me  SO 2CH 2COOEt    3-Cl          5-Cl     1-AI-Pip(4) 1693  4-F    Me  SO 2CH 2COOEt    3-Me          5-Me     1-AI-Pip(4) 1694  4-f    Me  SO 2CH 2COOEt    3-Cl          5-CONH 2 1-AI-Pip(4) 1695  4-F    Me  SO 2CH 2COOEt    2-Me          5-CONH 2 1-AI-Pip(4) 1696  4-F    Me  SO 2CH 2COOEt    3-Me          5-CONH 2 1-AI-Pip(4) 1697  4-F    Me  SO 2CH 2COOEt    3-CONH 2      5-CONH 2 1-AI-Pip(4) 1698  4-F    H   SO 2CH 2COOEt    H             H        1-AI-Pip(4) 1699  6-F    H   SO 2CH 2COOEt    H             H        1-AI-Pip(4) 1700  2-Cl   H   SO 2CH 2COOEt    H             H        1-AI-Pip(4) 1701  4-Cl   H   SO 2CH 2COOEt    H             H        1-AI-Pip(4) 1702  5-Cl   H   SO 2CH 2COOEt    H             H        1-AI-Pip(4) 1703  6-Cl   H   SO 2CH 2COOEt    H             H        1-AI-Pip(4) 1704  2-Br   H   SO 2CH 2COOEt    H             H        1-AI-Pip(4) 1705  4-Br   H   SO 2CH 2COOEt    H             H        1-AI-Pip(4) 1706  5-Br   H   SO 2CH 2COOEt    H             H        1-AI-Pip(4) 1707  6-Br   H   SO 2CH 2COOEt    H             H        1-AI-Pip(4) 1708  2-Me   H   SO 2CH 2COOEt    H             H        1-AI-Pip(4) 1709  3-Me   H   SO 2CH 2COOEt    H             H        1-AI-Pip(4) 1710  4-Me   H   SO 2CH 2COOEt    H             H        1-AI-Pip(4) 1711  5-Me   H   SO 2CH 2COOEt    H             H        1-AI-Pip(4) 1712  5-Me   H   SO 2CH 2COOEt    2-F           H        1-AI-Pip(4) 1713  5-Me   H   SO 2CH 2COOEt    3-F           H        1-AI-Pip(4) 1714  5-Me   H   SO 2CH 2COOEt    2-Cl          H        1-AI-Pip(4) 1715  5-Me   H   SO 2CH 2COOEt    3-Cl          H        1-AI-Pip(4) 1716  5-Me   H   SO 2CH 2COOEt    2-Br          H        1-AI-Pip(4) 1717  5-Me   H   SO 2CH 2COOEt    3-Br          H        1-AI-Pip(4) 1718  5-Me  H  SO 2CH 2COOEt    2-I        H    1-AI-Pip(4) 1719  5-Me  H  SO 2CH 2COOEt    3-I        H    1-AI-Pip(4) 1720  5-Me  H  SO 2CH 2COOEt    2-Me       H    1-AI-Pip(4) 1721  5-Me  H  SO 2CH 2COOEt    2-Me       H    1-AI-Pip(4) 1722  5-Me  H  SO 2CH 2COOEt    2-Et       H    1-AI-Pip(4) 1723  5-Me  H  SO 2CH 2COOEt    3-Et       H    1-AI-Pip(4) 1724  5-Me  H  SO 2CH 2COOEt    2-Pr       H    1-AI-Pip(4) 1725  5-Me  H  SO 2CH 2COOEt    3-Pr       H    1-AI-Pip(4) 1726  5-Me  H  SO 2CH 2COOEt    2-Bu       H    1-AI-Pip(4) 1727  5-Me  H  SO 2CH 2COOEt    3-Bu       H    1-AI-Pip(4) 1728  5-Me  H  SO 2CH 2COOEt    2-Pn       H    1-AI-Pip(4) 1729  5-Me  H  SO 2CH 2COOEt    3-Pn       H    1-AI-Pip(4) 1730  5-Me  H  SO 2CH 2COOEt    2-Hx       H    1-AI-Pip(4) 1731  5-Me  H  SO 2CH 2COOEt    3-Hx       H    1-AI-Pip(4) 1732  5-Me  H  SO 2CH 2COOEt    2-CF 3     H    1-AI-Pip(4) 1733  5-Me  H  SO 2CH 2COOEt    3-CF 3     H    1-AI-Pip(4) 1734  5-Me  H  SO 2CH 2COOEt    2-OMe      H    1-AI-Pip(4) 1735  5-Me  H  SO 2CH 2COOEt    3-OMe      H    1-AI-Pip(4) 1736  5-Me  H  SO 2CH 2COOEt    2-OEt      H    1-AI-Pip(4) 1737  5-Me  H  SO 2CH 2COOEt    3-OEt      H    1-AI-Pip(4) 1738  5-Me  H  SO 2CH 2COOEt    2-COOH     H    1-AI-Pip(4) 1739  5-Me  H  SO 2CH 2COOEt    3-COOH     H    1-AI-Pip(4) 1740  5-Me  H  SO 2CH 2COOEt    2-COOMe    H    1-AI-Pip(4) 1741  5-Me  H  SO 2CH 2COOEt    3-COOMe    H    1-AI-Pip(4) 1742  5-Me  H  SO 2CH 2COOEt    2-COOEt    H    1-AI-Pip(4) 1743  5-Me  H  SO 2CH 2COOEt    3-COOEt    H    1-AI-Pip(4) 1744  5-Me  H  SO 2CH 2COOEt    2-COOPr    H    1-AI-Pip(4) 1745  5-Me  H  SO 2CH 2COOEt    3-COOPr    H    1-AI-Pip(4) 1746  5-Me  H  SO 2CH 2COOEt    2-COOBu    H    1-AI-Pip(4) 1747  5-Me  H   SO 2CH 2COOEt    3-COOBu      H        1-AI-Pip(4) 1748  5-Me  H   SO 2CH 2COOEt    2-COOPn      H        1-AI-Pip(4) 1749  5-Me  H   SO 2CH 2COOEt    3-COOPn      H        1-AI-Pip(4) 1750  5-Me  H   SO 2CH 2COOEt    2-COOHx      H        1-AI-Pip(4) 1751  5-Me  H   SO 2CH 2COOEt    3-COOHx      H        1-AI-Pip(4) 1752  5-Me  H   SO 2CH 2COOEt    2-COMH 2     H        1-AI-Pip(4) 1753  5-Me  H   SO 2CH 2COOEt    3-CONH 2     H        1-AI-Pip(4) 1754  5-Me  H   SO 2CH 2COOEt    2-CONHMe     H        1-AI-Pip(4) 1755  5-Me  H   SO 2CH 2COOEt    3-CONHMe     H        1-AI-Pip(4) 1756  5-Me  H   SO 2CH 2COOEt    2-CONHEt     H        1-AI-Pip(4) 1757  5-Me  H   SO 2CH 2COOEt    3-CONHEt     H        1-AI-Pip(4) 1758  5-Me  H   SO 2CH 2COOEt    2-CON(Me) 2  H        1-AI-Pip(4) 1759  5-Me  H   SO 2CH 2COOEt    3-CON(Me) 2  H        1-AI-Pip(4) 1760  5-Me  H   SO 2CH 2COOEt    2-CON(Me)Et  H        1-AI-Pip(4) 1761  5-Me  H   SO 2CH 2COOEt    3-CON(Me)Et  H        1-AI-Pip(4) 1762  5-Me  H   SO 2CH 2COOEt    2-CON(Et) 2  H        1-AI-Pip(4) 1763  5-Me  H   SO 2CH 2COOEt    3-CON(Et) 2  H        1-AI-Pip(4) 1764  5-Me  Me  SO 2CH 2COOEt    3-F          5-F      1-AI-Pip(4) 1765  5-Me  Me  SO 2CH 2COOEt    3-Cl         5-Cl     1-AI-Pip(4) 1766  5-Me  Me  SO 2CH 2COOEt    3-Me         5-Me     1-AI-Pip(4) 1767  5-Me  Me  SO 2CH 2COOEt    3-Cl         5-CONH 2 1-AI-Pip(4) 1768  5-Me  Me  SO 2CH 2COOEt    2-Me         5-CONH 2 1-AI-Pip(4) 1769  5-Me  Me  SO 2CH 2COOEt    3-Me         5-CONH 2 1-AI-Pip(4) 1770  5-Me  Me  SO 2CH 2COOEt    3-CONH 2     5-CONH 2 1-AI-Pip(4) 1771  6-Me  H   SO 2CH 2COOEt    H            H        1-AI-Pip(4) 1772  6-Me  H   SO 2CH 2COOEt    2-F          H        1-AI-Pip(4) 1773  6-Me  H   SO 2CH 2COOEt    3-F          H        1-AI-Pip(4) 1774  6-Me  H   SO 2CH 2COOEt    2-Cl         H        1-AI-Pip(4) 1775  6-Me  H   SO 2CH 2COOEt    3-Cl         H        1-AI-Pip(4) 1776  6-Me  H  SO 2CH 2COOEt    2-Br       H    1-AI-Pip(4) 1777  6-Me  H  SO 2CH 2COOEt    3-Br       H    1-AI-Pip(4) 1778  6-Me  H  SO 2CH 2COOEt    2-I        H    1-AI-Pip(4) 1779  6-Me  H  SO 2CH 2COOEt    3-I        H    1-AI-Pip(4) 1780  6-Me  H  SO 2CH 2COOEt    2-Me       H    1-AI-Pip(4) 1781  6-Me  H  SO 2CH 2COOEt    3-Me       H    1-AI-Pip(4) 1782  6-Me  H  SO 2CH 2COOEt    2-Et       H    1-AI-Pip(4) 1783  6-Me  H  SO 2CH 2COOEt    3-Et       H    1-AI-Pip(4) 1784  6-Me  H  SO 2CH 2COOEt    2-Pr       H    1-AI-Pip(4) 1785  6-Me  H  SO 2CH 2COOEt    3-Pr       H    1-AI-Pip(4) 1786  6-Me  H  SO 2CH 2COOEt    2-Bu       H    1-AI-Pip(4) 1787  6-Me  H  SO 2CH 2COOEt    3-Bu       H    1-AI-Pip(4) 1788  6-Me  H  SO 2CH 2COOEt    2-Pn       H    1-AI-Pip(4) 1789  6-Me  H  SO 2CH 2COOEt    3-Pn       H    1-AI-Pip(4) 1790  6-Me  H  SO 2CH 2COOEt    2-Hx       H    1-AI-Pip(4) 1791  6-Me  H  SO 2CH 2COOEt    3-Hx       H    1-AI-Pip(4) 1792  6-Me  H  SO 2CH 2COOEt    2-CF 3     H    1-AI-Pip(4) 1793  6-Me  H  SO 2CH 2COOEt    3-CF 3     H    1-AI-Pip(4) 1794  6-Me  H  SO 2CH 2COOEt    2-OMe      H    1-AI-Pip(4) 1795  6-Me  H  SO 2CH 2COOEt    3-OMe      H    1-AI-Pip(4) 1796  6-Me  H  SO 2CH 2COOEt    2-OEt      H    1-AI-Pip(4) 1797  6-Me  H  SO 2CH 2COOEt    3-OEt      H    1-AI-Pip(4) 1798  6-Me  H  SO 2CH 2COOEt    2-COOH     H    1-AI-Pip(4) 1799  6-Me  H  SO 2CH 2COOEt    3-COOH     H    1-AI-Pip(4) 1800  6-Me  H  SO 2CH 2COOEt    2-COOMe    H    1-AI-Pip(4) 1801  6-Me  H  SO 2CH 2COOEt    3-COOMe    H    1-AI-Pip(4) 1802  6-Me  H  SO 2CH 2COOEt    2-COOEt    H    1-AI-Pip(4) 1803  6-Me  H  SO 2CH 2COOEt    3-COOEt    H    1-AI-Pip(4) 1804  6-Me  H  SO 2CH 2COOEt    2-COOPr    H    1-AI-Pip(4) 1805  6-Me  H  SO 2CH 2COOEt    3-COOPr      H         1-AI-Pip(4) 1806  6-Me  H  SO 2CH 2COOEt    2-COOBu      H         1-AI-Pip(4) 1807  6-Me  H  SO 2CH 2COOEt    3-COOBu      H         1-AI-Pip(4) 1808  6-Me  H  SO 2CH 2COOEt    2-COOPn      H         1-AI-Pip(4) 1809  6-Me  H  SO 2CH 2COOEt    3-COOPn      H         1-AI-Pip(4) 1810  6-Me  H  SO 2CH 2COOEt    2-COOHx      H         1-AI-Pip(4) 1811  6-Me  H  SO 2CH 2COOEt    3-COOHx      H         1-AI-Pip(4) 1812  6-Me  H  SO 2CH 2COOEt    2-CONH 2     H         1-AI-Pip(4) 1813  6-Me  H  SO 2CH 2COOEt    3-CONH 2     H         1-AI-Pip(4) 1814  6-Me  H  SO 2CH 2COOEt    2-CONHMe     H         1-AI-Pip(4) 1815  6-Me  H  SO 2CH 2COOEt    3-COHMe      H         1-AI-Pip(4) 1816  6-Me  H  SO 2CH 2COOEt    2-CONHEt     H         1-AI-Pip(4) 1817  6-Me  H  SO 2CH 2COOEt    3-CONHEt     H         1-AI-Pip(4) 1818  6-Me  H  SO 2CH 2COOEt    2-CON(Me) 2  H         1-AI-Pip(4) 1819  6-Me  H  SO 2CH 2COOEt    3-CON(Me) 2  H         1-AI-Pip(4) 1820  6-Me  H  SO 2CH 2COOEt    2-CON(Me)Et  H         1-AI-Pip(4) 1821  6-Me  H  SO 2CH 2COOEt    3-CON(Me)Et  H         1-AI-Pip(4) 1822  6-Me  H  SO 2CH 2COOEt    2-CON(Me) 2  H         1-AI-Pip(4) 1823  6-Me  H  SO 2CH 2COOEt    3-CON(Et) 2  H         1-AI-Pip(4) 1824  6-Me  Me SO 2CH 2COOEt    3-F          5-F       1-AI-Pip(4) 1825  6-Me  Me SO 2CH 2COOEt    3-Cl         5-Cl      1-AI-Pip(4) 1826  6-Me  Me SO 2CH 2COOEt    3-Me         5-Me      1-AI-Pip(4) 1827  6-Me  Me SO 2CH 2COOEt    3-Cl         5-CONH 2  1-AI-Pip(4) 1828  6-Me  Me SO 2CH 2COOEt    2-Me         5-CONH 2  1-AI-Pip(4) 1829  6-Me  Me SO 2CH 2COOEt    3-Me         5-CONH 2  1-AI-Pip(4) 1830  6-Me  Me SO 2CH 2COOEt    3-CONH 2     5-CONH 2  1-AI-Pip(4) 1831  2-Et  H  SO 2CH 2COOEt    H            H         1-AI-Pip(4) 1832  6-Me  H  SO 2CH 2COOEt    H            H         1-AI-Pip(4) 1833  6-Me  H  SO 2CH 2COOEt    H            H         1-AI-Pip(4) 1834  6-Et  H  SO 2CH 2COOEt    H        H    1-AI-Pip(4) 1835  2-Pr  H  SO 2CH 2COOEt    H        H    1-AI-Pip(4) 1836  4-Bu  H  SO 2CH 2COOEt    H        H    1-AI-Pip(4) 1837  5-Pn  H  SO 2CH 2COOEt    H        H    1-AI-Pip(4) 1838  6-Hx  H  SO 2CH 2COOEt    H        H    1-AI-Pip(4) 1839  6-OH  H  SO 2CH 2COOEt    H        H    1-AI-Pip(4) 1840  6-OH  H  SO 2CH 2COOEt    2-F      H    1-AI-Pip(4) 1841  6-OH  H  SO 2CH 2COOEt    3-F      H    1-AI-Pip(4) 1842  6-OH  H  SO 2CH 2COOEt    2-Cl     H    1-AI-Pip(4) 1843  6-OH  H  SO 2CH 2COOEt    3-Cl     H    1-AI-Pip(4) 1844  6-OH  H  SO 2CH 2COOEt    2-Br     H    1-AI-Pip(4) 1845  6-OH  H  SO 2CH 2COOEt    3-Br     H    1-AI-Pip(4) 1846  6-OH  H  SO 2CH 2COOEt    2-I      H    1-AI-Pip(4) 1847  6-OH  H  SO 2CH 2COOEt    3-I      H    1-AI-Pip(4) 1848  6-OH  H  SO 2CH 2COOEt    2-Me     H    1-AI-Pip(4) 1849  6-OH  H  SO 2CH 2COOEt    3-Me     H    1-AI-Pip(4) 1850  6-OH  H  SO 2CH 2COOEt    2-Et     H    1-AI-Pip(4) 1851  6-OH  H  SO 2CH 2COOEt    3-Et     H    1-AI-Pip(4) 1852  6-OH  H  SO 2CH 2COOEt    2-Pr     H    1-AI-Pip(4) 1853  6-OH  H  SO 2CH 2COOEt    3-Pr     H    1-AI-Pip(4) 1854  6-OH  H  SO 2CH 2COOEt    2-Bu     H    1-AI-Pip(4) 1855  6-OH  H  SO 2CH 2COOEt    3-Bu     H    1-AI-Pip(4) 1856  6-OH  H  SO 2CH 2COOEt    2-Pn     H    1-AI-Pip(4) 1857  6-OH  H  SO 2CH 2COOEt    3-Pn     H    1-AI-Pip(4) 1858  6-OH  H  SO 2CH 2COOEt    2-Hx     H    1-AI-Pip(4) 1859  6-OH  H  SO 2CH 2COOEt    3-Hx     H    1-AI-Pip(4) 1860  6-OH  H  SO 2CH 2COOEt    2-CF 3   H    1-AI-Pip(4) 1861  6-OH  H  SO 2CH 2COOEt    3-CF 3   H    1-AI-Pip(4) 1862  6-OH  H  SO 2CH 2COOEt    2-OMe    H    1-AI-Pip(4) 1863  6-OH  H  SO 2CH 2COOEt    3-OMe         H    1-AI-Pip(4) 1864  6-OH  H  SO 2CH 2COOEt    2-OEt         H    1-AI-Pip(4) 1865  6-OH  H  SO 2CH 2COOEt    3-OEt         H    1-AI-Pip(4) 1866  6-OH  H  SO 2CH 2COOEt    2-COOH        H    1-AI-Pip(4) 1867  6-OH  H  SO 2CH 2COOEt    3-COOH        H    1-AI-Pip(4) 1868  6-OH  H  SO 2CH 2COOEt    2-COOMe       H    1-AI-Pip(4) 1869  6-OH  H  SO 2CH 2COOEt    3-COOMe       H    1-AI-Pip(4) 1870  6-OH  H  SO 2CH 2COOEt    2-COOEt       H    1-AI-Pip(4) 1871  6-OH  H  SO 2CH 2COOEt    3-COOEt       H    1-AI-Pip(4) 1872  6-OH  H  SO 2CH 2COOEt    2-COOPr       H    1-AI-Pip(4) 1873  6-OH  H  SO 2CH 2COOEt    3-COOPr       H    1-AI-Pip(4) 1874  6-OH  H  SO 2CH 2COOEt    2-COOBu       H    1-AI-Pip(4) 1875  6-OH  H  SO 2CH 2COOEt    3-COOBu       H    1-AI-Pip(4) 1876  6-OH  H  SO 2CH 2COOEt    2-COOPn       H    1-AI-Pip(4) 1877  6-OH  H  SO 2CH 2COOEt    3-COOPn       H    1-AI-Pip(4) 1878  6-OH  H  SO 2CH 2COOEt    2-COOHx       H    1-AI-Pip(4) 1879  6-OH  H  SO 2CH 2COOEt    3-COOHx       H    1-AI-Pip(4) 1880  6-OH  H  SO 2CH 2COOEt    2-CONH 2      H    1-AI-Pip(4) 1881  6-OH  H  SO 2CH 2COOEt    3-CONH 2      H    1-AI-Pip(4) 1882  6-OH  H  SO 2CH 2COOEt    2-CONHMe      H    1-AI-Pip(4) 1883  6-OH  H  SO 2CH 2COOEt    3-CONHMe      H    1-AI-Pip(4) 1884  6-OH  H  SO 2CH 2COOEt    2-CONHEt      H    1-AI-Pip(4) 1885  6-OH  H  SO 2CH 2COOEt    3-CONHEt      H    1-AI-Pip(4) 1886  6-OH  H  SO 2CH 2COOEt    2-CON(Me) 2   H    1-AI-Pip(4) 1887  6-OH  H  SO 2CH 2COOEt    3-CON(Me) 2   H    1-AI-Pip(4) 1888  6-OH  H  SO 2CH 2COOEt    2-CON(Me)Et   H    1-AI-Pip(4) 1889  6-OH  H  SO 2CH 2COOEt    3-CON(Me)Et   H    1-AI-Pip(4) 1890  6-OH  H  SO 2CH 2COOEt    2-CON(Et) 2   H    1-AI-Pip(4) 1891  6-OH  H  SO 2CH 2COOEt    3-CON(Et) 2   H    1-AI-Pip(4) 1892  6-OH  H  SO 2CH 2COOEt    2-F    3-F       1-AI-Pip(4) 1893  6-OH  H  SO 2CH 2COOEt    2-F    5-F       1-AI-Pip(4) 1894  6-OH  H  SO 2CH 2COOEt    2-F    6-F       1-AI-Pip(4) 1895  6-OH  H  SO 2CH 2COOEt    3-F    5-F       1-AI-Pip(4) 1896  6-OH  H  SO 2CH 2COOEt    2-Cl   3-Cl      1-AI-Pip(4) 1897  6-OH  H  SO 2CH 2COOEt    2-Cl   5-Cl      1-AI-Pip(4) 1898  6-OH  H  SO 2CH 2COOEt    2-Cl   6-Cl      1-AI-Pip(4) 1899  6-OH  H  SO 2CH 2COOEt    3-Cl   5-Cl      1-AI-Pip(4) 1900  6-OH  H  SO 2CH 2COOEt    2-Me   3-Me      1-AI-Pip(4) 1901  6-OH  H  SO 2CH 2COOEt    2-Me   5-Me      1-AI-Pip(4) 1902  6-OH  H  SO 2CH 2COOEt    2-Me   6-Me      1-AI-Pip(4) 1903  6-OH  H  SO 2CH 2COOEt    3-Me   5-Me      1-AI-Pip(4) 1904  6-OH  H  SO 2CH 2COOEt    2-Cl   5-CONH 2  1-AI-Pip(4) 1905  6-OH  H  SO 2CH 2COOEt    3-Cl   5-CONH 2  1-AI-Pip(4) 1906  6-OH  H  SO 2CH 2COOEt    3-Cl   5-CONHMe  1-AI-Pip(4) 1907  6-OH  H  SO 2CH 2COOEt    3-Cl   5-CONHEt  1-AI-Pip(4) 1908  6-OH  H  SO 2CH 2COOEt    3-Cl   5-CONHPr  1-AI-Pip(4) 1909  6-OH  H  SO 2CH 2COOEt    3-Cl   5-CONHBu  1-AI-Pip(4) 1910  6-OH  H  SO 2CH 2COOEt    3-Cl   5-CONHPn  1-AI-Pip(4) 1911  6-OH  H  SO 2CH 2COOEt    3-Cl   5-CONHHx  1-AI-Pip(4) 1912  6-OH  H  SO 2CH 2COOEt    2-Me   5-CONH 2  1-AI-Pip(4) 1913  6-OH  H  SO 2CH 2COOEt    2-Me   5-CONHMe  1-AI-Pip(4) 1914  6-OH  H  SO 2CH 2COOEt    2-Me   5-CONHEt  1-AI-Pip(4) 1915  6-OH  H  SO 2CH 2COOEt    2-Me   5-CONHPr  1-AI-Pip(4) 1916  6-OH  H  SO 2CH 2COOEt    2-Me   5-CONHBu  1-AI-Pip(4) 1917  6-OH  H  SO 2CH 2COOEt    2-Me   5-CONHPn  1-AI-Pip(4) 1918  6-OH  H  SO 2CH 2COOEt    2-Me   5-CONHHx  1-AI-Pip(4) 1919  6-OH  H  SO 2CH 2COOEt    3-Me   5-CONH 2  1-AI-Pip(4) 1920  6-OH  H  SO 2CH 2COOEt    3-Me   5-CONHMe  1-AI-Pip(4) 1921  6-OH  H  SO 2CH 2COOEt       3-Me        5-CONHEt   1-AI-Pip(4) 1922  6-OH  H  SO 2CH 2COOEt       3-Me        5-CONHPr   1-AI-Pip(4) 1923  6-OH  H  SO 2CH 2COOEt       3-Me        5-CONHBu   1-AI-Pip(4) 1924  6-OH  H  SO 2CH 2COOEt       3-Me        5-CONHPn   1-AI-Pip(4) 1925  6-OH  H  SO 2CH 2COOEt       3-Me        5-CONHHx   1-AI-Pip(4) 1926  6-OH  H  SO 2CH 2COOEt       2-CONH 2    6-CONH 2   1-AI-Pip(4) 1927  6-OH  H  SO 2CH 2COOEt       3-CONH 2    5-ONH 2    1-AI-Pip(4) 1928  6-OH  H  SO 2CH 2COOEt       3-CONHMe    5-CONHMe   1-AI-Pip(4) 1929  6-OH  H  SO 2CH 2COOEt       3-CONHEt    5-CONHEt   1-AI-Pip(4) 1930  H     H  SO 2CH 2COOPr       H           H          1-AI-Pip(4) 1931  H     H  SO 2CH 2COOBu       H           H          1-AI-Pip(4) 1932  H     H  SO 2CH 2COOPn       H           H          1-AI-Pip(4) 1933  H     H  SO 2CH 2COOHx       H           H          1-AI-Pip(4) 1934  H     H  SO 2(CH 2) 2COOEt   H           H          1-AI-Pip(4) 1935  H     H  SO 2(CH 2) 3COOEt   H           H          1-AI-Pip(4) 1936  H     H  SO 2(CH 2) 4COOEt   H           H          1-AI-Pip(4) 1937  H     H  SO 2(CH 2) 5COOEt   H           H          1-AI-Pip(4) 1938  H     H  SO 2(CH 2) 6COOEt   H           H          1-AI-Pip(4) 1939  H     H  SO 2CH 2COOH        H           H          1-AI-Pip(4) 1940  H     H  SO 2CH 2COOH        2-F         H          1-AI-Pip(4) 1941  H     H  SO 2CH 2COOH        3-F         H          1-AI-Pip(4) 1942  H     H  SO 2CH 2COOH        2-Cl        H          1-AI-Pip(4) 1943  H     H  SO 2CH 2COOH        3-Cl        H          1-AI-Pip(4) 1944  H     H  SO 2CH 2COOH        2-Br        H          1-AI-Pip(4) 1945  H     H  SO 2CH 2COOH        3-Br        H          1-AI-Pip(4) 1946  H     H  SO 2CH 2COOH        2-I         H          1-AI-Pip(4) 1947  H     H  SO 2CH 2COOH        3-I         H          1-AI-Pip(4) 1948  H     H  SO 2CH 2COOH        2-Me        H          1-AI-Pip(4) 1949  H     H  SO 2CH 2COOH        3-Me        H          1-AI-Pip(4) 1950  H    H  SO 2CH 2COOH    2-Et       H    1-AI-Pip(4) 1951  H    H  SO 2CH 2COOH    3-Et       H    1-AI-Pip(4) 1952  H    H  SO 2CH 2COOH    2-Pr       H    1-AI-Pip(4) 1953  H    H  SO 2CH 2COOH    3-Pr       H    1-AI-Pip(4) 1954  H    H  SO 2CH 2COOH    2- iPr    H    1-AI-Pip(4) 1955  H    H  SO 2CH 2COOH    3- iPr    H    1-AI-Pip(4) 1956  H    H  SO 2CH 2COOH    2-Bu       H    1-AI-Pip(4) 1957  H    H  SO 2CH 2COOH    3-Bu       H    1-AI-Pip(4) 1958  H    H  SO 2CH 2COOH    2- iBu    H    1-AI-Pip(4) 1959  H    H  SO 2CH 2COOH    3- iBu    H    1-AI-Pip(4) 1960  H    H  SO 2CH 2COOH    2- sBu    H    1-AI-Pip(4) 1961  H    H  SO 2CH 2COOH    3- sBu    H    1-AI-Pip(4) 1962  H    H  SO 2CH 2COOH    2- tBu    H    1-AI-Pip(4) 1963  H    H  SO 2CH 2COOH    3- tBu    H    1-AI-Pip(4) 1964  H    H  SO 2CH 2COOH    2-Pn       H    1-AI-Pip(4) 1965  H    H  SO 2CH 2COOH    3-Pn       H    1-AI-Pip(4) 1966  H    H  SO 2CH 2COOH    2-Hx       H    1-AI-Pip(4) 1967  H    H  SO 2CH 2COOH    3-Hx       H    1-AI-Pip(4) 1968  H    H  SO 2CH 2COOH    2-CF 3     H    1-AI-Pip(4) 1969  H    H  SO 2CH 2COOH    3-CF 3     H    1-AI-Pip(4) 1970  H    H  SO 2CH 2COOH    2-OMe      H    1-AI-Pip(4) 1971  H    H  SO 2CH 2COOH    3-OMe      H    1-AI-Pip(4) 1972  H    H  SO 2CH 2COOH    2-OEt      H    1-AI-Pip(4) 1973  H    H  SO 2CH 2COOH    3-OEt      H    1-AI-Pip(4) 1974  H    H  SO 2CH 2COOH    2-COOH     H    1-AI-Pip(4) 1975  H    H  SO 2CH 2COOH    3-COOH     H    1-AI-Pip(4) 1976  H    H  SO 2CH 2COOH    2-COOMe    H    1-AI-Pip(4) 1977  H    H  SO 2CH 2COOH    3-COOMe    H    1-AI-Pip(4) 1978  H    H  SO 2CH 2COOH    2-COOEt    H    1-AI-Pip(4) 1979  H    H  SO 2CH 2COOH    3-COOEt       H      1-AI-Pip(4) 1980  H    H  SO 2CH 2COOH    2-COOPr       H      1-AI-Pip(4) 1981  H    H  SO 2CH 2COOH    3-COOPr       H      1-AI-Pip(4) 1982  H    H  SO 2CH 2COOH    2-COOBu       H      1-AI-Pip(4) 1983  H    H  SO 2CH 2COOH    3-COOBu       H      1-AI-Pip(4) 1984  H    H  SO 2CH 2COOH    2-COOPn       H      1-AI-Pip(4) 1985  H    H  SO 2CH 2COOH    3-COOPn       H      1-AI-Pip(4) 1986  H    H  SO 2CH 2COOH    2-COOHx       H      1-AI-Pip(4) 1987  H    H  SO 2CH 2COOH    3-COOHx       H      1-AI-Pip(4) 1988  H    H  SO 2CH 2COOH    2-CONH 2      H      1-AI-Pip(4) 1989  H    H  SO 2CH 2COOH    3-CONH 2      H      1-AI-Pip(4) 1990  H    H  SO 2CH 2COOH    2-CONHMe      H      1-AI-Pip(4) 1991  H    H  SO 2CH 2COOH    3-CONHMe      H      1-AI-Pip(4) 1992  H    H  SO 2CH 2COOH    2-CONHEt      H      1-AI-Pip(4) 1993  H    H  SO 2CH 2COOH    3-CONHEt      H      1-AI-Pip(4) 1994  H    H  SO 2CH 2COOH    2-CON(Me) 2   H      1-AI-Pip(4) 1995  H    H  SO 2CH 2COOH    3-CON(Me) 2   H      1-AI-Pip(4) 1996  H    H  SO 2CH 2COOH    2-CON(Me)Et   H      1-AI-Pip(4) 1997  H    H  SO 2CH 2COOH    3-CON(Me)Et   H      1-AI-Pip(4) 1998  H    H  SO 2CH 2COOH    2-CON(Et) 2   H      1-AI-Pip(4) 1999  H    H  SO 2CH 2COOH    3-CON(Et) 2   H      1-AI-Pip(4) 2000  H    H  SO 2CH 2COOH    2-F           3-F    1-AI-Pip(4) 2001  H    H  SO 2CH 2COOH    2-F           5-F    1-AI-Pip(4) 2002  H    H  SO 2CH 2COOH    2-F           6-F    1-AI-Pip(4) 2003  H    H  SO 2CH 2COOH    3-F           5-F    1-AI-Pip(4) 2004  H    H  SO 2CH 2COOH    2-Cl          3-Cl   1-AI-Pip(4) 2005  H    H  SO 2CH 2COOH    2-Cl          5-Cl   1-AI-Pip(4) 2006  H    H  SO 2CH 2COOH    2-Cl          6-Cl   1-AI-Pip(4) 2007  H    H  SO 2CH 2COOH    3-Cl          5-Cl   1-AI-Pip(4) 2008  H    H  SO 2CH 2COOH    2-Me       3-Me      1-AI-Pip(4) 2009  H    H  SO 2CH 2COOH    2-Me       5-Me      1-AI-Pip(4) 2010  H    H  SO 2CH 2COOH    2-Me       6-Me      1-AI-Pip(4) 2011  H    H  SO 2CH 2COOH    3-Me       5-Me      1-AI-Pip(4) 2012  H    H  SO 2CH 2COOH    2-Cl       5-CONH 2  1-AI-Pip(4) 2013  H    H  SO 2CH 2COOH    3-Cl       5-CONH 2  1-AI-Pip(4) 2014  H    H  SO 2CH 2COOH    3-Cl       5-CONHMe  1-AI-Pip(4) 2015  H    H  SO 2CH 2COOH    3-Cl       5-CONHEt  1-AI-Pip(4) 2016  H    H  SO 2CH 2COOH    3-Cl       5-CONHPr  1-AI-Pip(4) 2017  H    H  SO 2CH 2COOH    3-Cl       5-CONHBu  1-AI-Pip(4) 2018  H    H  SO 2CH 2COOH    3-Cl       5-CONHPn  1-AI-Pip(4) 2019  H    H  SO 2CH 2COOH    3-Cl       5-CONHHx  1-AI-Pip(4) 2020  H    H  SO 2CH 2COOH    2-Me       5-CONH 2  1-AI-Pip(4) 2021  H    H  SO 2CH 2COOH    2-Me       5-CONHMe  1-AI-Pip(4) 2022  H    H  SO 2CH 2COOH    2-Me       5-CONHEt  1-AI-Pip(4) 2023  H    H  SO 2CH 2COOH    2-Me       5-CONHPr  1-AI-Pip(4) 2024  H    H  SO 2CH 2COOH    2-Me       5-CONHBu  1-AI-Pip(4) 2025  H    H  SO 2CH 2COOH    2-Me       5-CONHPn  1-AI-Pip(4) 2026  H    H  SO 2CH 2COOH    2-Me       5-CONHHx  1-AI-Pip(4) 2027  H    H  SO 2CH 2COOH    3-Me       5-CONH 2  1-AI-Pip(4) 2028  H    H  SO 2CH 2COOH    3-Me       5-CONHMe  1-AI-Pip(4) 2029  H    H  SO 2CH 2COOH    3-Me       5-CONHEt  1-AI-Pip(4) 2030  H    H  SO 2CH 2COOH    3-Me       5-CONHPr  1-AI-Pip(4) 2031  H    H  SO 2CH 2COOH    3-Me       5-CONHBu  1-AI-Pip(4) 2032  H    H  SO 2CH 2COOH    3-Me       5-CONHPn  1-AI-Pip(4) 2033  H    H  SO 2CH 2COOH    3-Me       5-CONHHx  1-AI-Pip(4) 2034  H    H  SO 2CH 2COOH    2-CONH 2   6-CONH 2  1-AI-Pip(4) 2035  H    H  SO 2CH 2COOH    3-CONH 2   5-CONH 2  1-AI-Pip(4) 2036  H    H  SO 2CH 2COOH    3-CONHMe   5-CONHMe  1-AI-Pip(4) 2037  H    H  SO 2CH 2COOH    3-CONHEt   5-CONHEt  1-AI-Pip(4) 2038  H    F  SO 2CH 2COOH    H          H         1-AI-Pip(4) 2039  H    F  SO 2CH 2COOH    2-F        H         1-AI-Pip(4) 2040  H    F  SO 2CH 2COOH    3-F        H         1-AI-Pip(4) 2041  H    F  SO 2CH 2COOH    2-Cl       H         1-AI-Pip(4) 2042  H    F  SO 2CH 2COOH    3-Cl       H         1-AI-Pip(4) 2043  H    F  SO 2CH 2COOH    2-Br       H         1-AI-Pip(4) 2044  H    F  SO 2CH 2COOH    3-Br       H         1-AI-Pip(4) 2045  H    F  SO 2CH 2COOH    2-I        H         1-AI-Pip(4) 2046  H    F  SO 2CH 2COOH    3-I        H         1-AI-Pip(4) 2047  H    F  SO 2CH 2COOH    2-Me       H         1-AI-Pip(4) 2048  H    F  SO 2CH 2COOH    3-Me       H         1-AI-Pip(4) 2049  H    F  SO 2CH 2COOH    2-Et       H         1-AI-Pip(4) 2050  H    F  SO 2CH 2COOH    3-Et       H         1-AI-Pip(4) 2051  H    F  SO 2CH 2COOH    2-Pr       H         1-AI-Pip(4) 2052  H    F  SO 2CH 2COOH    3-Pr       H         1-AI-Pip(4) 2053  H    F  SO 2CH 2COOH    2- iPr    H         1-AI-Pip(4) 2054  H    F  SO 2CH 2COOH    3- iPr    H         1-AI-Pip(4) 2055  H    F  SO 2CH 2COOH    2-Bu       H         1-AI-Pip(4) 2056  H    F  SO 2CH 2COOH    3-Bu       H         1-AI-Pip(4) 2057  H    F  SO 2CH 2COOH    2- iBu    H         1-AI-Pip(4) 2058  H    F  SO 2CH 2COOH    3- iBu    H         1-AI-Pip(4) 2059  H    F  SO 2CH 2COOH    2- sBu    H         1-AI-Pip(4) 2060  H    F  SO 2CH 2COOH    3- sBu    H         1-AI-Pip(4) 2061  H    F  SO 2CH 2COOH    2- tBu    H         1-AI-Pip(4) 2062  H    F  SO 2CH 2COOH    3- tBu    H         1-AI-Pip(4) 2063  H    F  SO 2CH 2COOH    2-Pn       H         1-AI-Pip(4) 2064  H    F  SO 2CH 2COOH    3-Pn       H         1-AI-Pip(4) 2065  H    F  SO 2CH 2COOH    2-Hx       H         1-AI-Pip(4) 2066  H    F    SO 2CH 2COOH    3-Hx          H    1-AI-Pip(4) 2067  H    F    SO 2CH 2COOH    2-CF 3        H    1-AI-Pip(4) 2068  H    F    SO 2CH 2COOH    3-CF 3        H    1-AI-Pip(4) 2069  H    F    SO 2CH 2COOH    2-OMe         H    1-AI-Pip(4) 2070  H    F    SO 2CH 2COOH    3-OMe         H    1-AI-Pip(4) 2071  H    F    SO 2CH 2COOH    2-OEt         H    1-AI-Pip(4) 2072  H    F    SO 2CH 2COOH    3-OEt         H    1-AI-Pip(4) 2073  H    F    SO 2CH 2COOH    2-COOH        H    1-AI-Pip(4) 2074  H    F    SO 2CH 2COOH    3-COOH        H    1-AI-Pip(4)  2075  H    F    SO 2CH 2COOH    2-COOMe       H    1-AI-Pip(4) 2076  H    F    SO 2CH 2COOH    3-COOMe       H    1-AI-Pip(4) 2077  H    F    SO 2CH 2COOH    2-COOEt       H    1-AI-Pip(4) 2078  H    F    SO 2CH 2COOH    3-COOEt       H    1-AI-Pip(4) 2079  H    F    SO 2CH 2COOH    2-COOPr       H    1-AI-Pip(4) 2080  H    F    SO 2CH 2COOH    3-COOPr       H    1-AI-Pip(4) 2081  H    F    SO 2CH 2COOH    2-COOBu       H    1-AI-Pip(4) 2082  H    F    SO 2CH 2COOH    3-COOBu       H    1-AI-Pip(4) 2083  H    F    SO 2CH 2COOH    2-COOPn       H    1-AI-Pip(4) 2084  H    F    SO 2CH 2COOH    3-COOPn       H    1-AI-Pip(4) 2085  H    F    SO 2CH 2COOH    2-COOHx       H    1-AI-Pip(4) 2086  H    F    SO 2CH 2COOH    3-COOHx       H    1-AI-Pip(4) 2087  H    F    SO 2CH 2COOH    2-CONH 2      H    1-AI-Pip(4) 2088  H    F    SO 2CH 2COOH    3-CONH 2      H    1-AI-Pip(4) 2089  H    F    SO 2CH 2COOH    2-CONHMe      H    1-AI-Pip(4) 2090  H    F    SO 2CH 2COOH    3-CONHMe      H    1-AI-Pip(4) 2091  H    F    SO 2CH 2COOH    2-CONHEt      H    1-AI-Pip(4) 2092  H    F    SO 2CH 2COOH    3-CONHEt      H    1-AI-Pip(4) 2093  H    F    SO 2CH 2COOH    2-CON(Me) 2   H    1-AI-Pip(4) 2094  H    E    SO 2CH 2COOH    3-CON(Me) 2   H    1-AI-Pip(4) 2095  H    F   SO 2CH 2COOH    2-CON(Me)Et   H    1-AI-Pip(4) 2096  H    F   SO 2CH 2COOH    3-CON(Me)Et   H    1-AI-Pip(4) 2097  H    F   SO 2CH 2COOH    2-CON(Et) 2   H    1-AI-Pip(4) 2098  H    F   SO 2CH 2COOH    3-CON(Et) 2   H    1-AI-Pip(4) 2099  H    Me  SO 2CH 2COOH    H             H    1-AI-Pip(4) 2100  H    Me  SO 2CH 2COOH    2-F           H    1-AI-Pip(4) 2101  H    Me  SO 2CH 2COOH    3-F           H    1-AI-Pip(4) 2102  H    Me  SO 2CH 2COOH    2-Cl          H    1-AI-Pip(4) 2103  H    Me  SO 2CH 2COOH    3-Cl          H    1-AI-Pip(4) 2104  H    Me  SO 2CH 2COOH    2-Br          H    1-AI-Pip(4) 2105  H    Me  SO 2CH 2COOH    3-Br          H    1-AI-Pip(4) 2106  H    Me  SO 2CH 2COOH    2-I           H    1-AI-Pip(4) 2107  H    Me  SO 2CH 2COOH    3-I           H    1-AI-Pip(4) 2108  H    Me  SO 2CH 2COOH    2-Me          H    1-AI-Pip(4) 2109  H    Me  SO 2CH 2COOH    3-Me          H    1-AI-Pip(4) 2110  H    Me  SO 2CH 2COOH    2-Et          H    1-AI-Pip(4) 2111  H    Me  SO 2CH 2COOH    3-Et          H    1-AI-Pip(4) 2112  H    Me  SO 2CH 2COOH    2-Pr          H    1-AI-Pip(4) 2113  H    Me  SO 2CH 2COOH    3-Bu          H    1-AI-Pip(4) 2114  H    Me  SO 2CH 2COOH    2-Bu          H    1-AI-Pip(4) 2115  H    Me  SO 2CH 2COOH    3-Bu          H    1-AI-Pip(4) 2116  H    Me  SO 2CH 2COOH    2-Pn          H    1-AI-Pip(4) 2117  H    Me  SO 2CH 2COOH    3-Pn          H    1-AI-Pip(4) 2118  H    Me  SO 2CH 2COOH    2-Hx          H    1-AI-Pip(4) 2119  H    Me  SO 2CH 2COOH    3-Hx          H    1-AI-Pip(4) 2120  H    Me  SO 2CH 2COOH    2-CF 3        H    1-AI-Pip(4) 2121  H    Me  SO 2CH 2COOH    3-CF 3        H    1-AI-Pip(4) 2122  H    Me  SO 2CH 2COOH    2-OMe         H    1-AI-Pip(4) 2123  H    Me  SO 2CH 2COOH    3-OMe         H    11-AI-Pip(4) 2124  H    Me  SO 2CH 2COOH    2-OEt        H    1-AI-Pip(4) 2125  H    Me  SO 2CH 2COOH    3-OEt        H    1-AI-Pip(4) 2126  H    Me  SO 2CH 2COOH    2-COOH       H    1-AI-Pip(4) 2127  H    Me  SO 2CH 2COOH    3-COOH       H    1-AI-Pip(4) 2128  H    Me  SO 2CH 2COOH    2-COOMe      H    1-AI-Pip(4) 2129  H    Me  SO 2CH 2COOH    3-COOMe      H    1-AI-Pip(4) 2130  H    Me  SO 2CH 2COOH    2-COOEt      H    1-AI-Pip(4) 2131  H    Me  SO 2CH 2COOH    3-COOEt      H    1-AI-Pip(4) 2132  H    Me  SO 2CH 2COOH    2-COOPr      H    1-AI-Pip(4) 2133  H    Me  SO 2CH 2COOH    3-COOPr      H    1-AI-Pip(4) 2134  H    Me  SO 2CH 2COOH    2-COOBu      H    1-AI-Pip(4) 2135  H    Me  SO 2CH 2COOH    3-COOBu      H    1-AI-Pip(4) 2136  H    Me  SO 2CH 2COOH    2-COOPn      H    1-AI-Pip(4) 2137  H    Me  SO 2CH 2COOH    3-COOPn      H    1-AI-Pip(4) 2138  H    Me  SO 2CH 2COOH    2-COOHx      H    1-AI-Pip(4) 2139  H    Me  SO 2CH 2COOH    3-COOHx      H    1-AI-Pip(4) 2140  H    Me  SO 2CH 2COOH    2-CONH 2     H    1-AI-Pip(4) 2141  H    Me  SO 2CH 2COOH    3-CONH 2     H    1-AI-Pip(4) 2142  H    Me  SO 2CH 2COOH    2-CONHMe     H    1-AI-Pip(4) 2143  H    Me  SO 2CH 2COOH    3-CONHMe     H    1-AI-Pip(4) 2144  H    Me  SO 2CH 2COOH    2-CONHEt     H    1-AI-Pip(4) 2145  H    Me  SO 2CH 2COOH    3-CONHEt     H    1-AI-Pip(4) 2146  H    Me  SO 2CH 2COOH    2-CON(Me) 2  H    1-AI-Pip(4) 2147  H    Me  SO 2CH 2COOH    3-CON(Me) 2  H    1-AI-Pip(4) 2148  H    Me  SO 2CH 2COOH    2-CON(Me)Et  H    1-AI-Pip(4) 2149  H    Me  SO 2CH 2COOH    3-CON(Me)Et  H    1-AI-Pip(4) 2150  H    Me  SO 2CH 2COOH    2-CON(Et) 2  H    1-AI-Pip(4) 2151  H    Me  SO 2CH 2COOH    3-CON(Et) 2  H    1-AI-Pip(4) 2152  6-F  H   SO 2CH 2COOH    H            H    1-AI-Pip(4) 2153  6-F    H  SO 2CH 2COOH    2-F      H    1-AI-Pip(4) 2154  6-F    H  SO 2CH 2COOH    3-F      H    1-AI-Pip(4) 2155  6-F    H  SO 2CH 2COOH    2-Cl     H    1-AI-Pip(4) 2156  6-F    H  SO 2CH 2COOH    3-Cl     H    1-AI-Pip(4) 2157  6-F    H  SO 2CH 2COOH    2-Br     H    1-AI-Pip(4) 2158  6-F    H  SO 2CH 2COOH    3-Br     H    1-AI-Pip(4) 2159  6-F    H  SO 2CH 2COOH    2-I      H    1-AI-Pip(4) 2160  6-F    H  SO 2CH 2COOH    3-I      H    1-AI-Pip(4) 2161  6-F    H  SO 2CH 2COOH    2-Me     H    1-AI-Pip(4) 2162  6-F    H  SO 2CH 2COOH    3-Me     H    1-AI-Pip(4) 2163  6-F    H  SO 2CH 2COOH    2-Et     H    1-AI-Pip(4) 2164  6-F    H  SO 2CH 2COOH    3-Et     H    1-AI-Pip(4) 2165  6-F    H  SO 2CH 2COOH    2-Pr     H    1-AI-Pip(4) 2166  6-F    H  SO 2CH 2COOH    3-Pr     H    1-AI-Pip(4) 2167  6-F    H  SO 2CH 2COOH    2-Bu     H    1-AI-Pip(4) 2168  6-F    H  SO 2CH 2COOH    3-Bu     H    1-AI-Pip(4) 2169  6-F    H  SO 2CH 2COOH    2-Pn     H    1-AI-Pip(4) 2170  6-F    H  SO 2CH 2COOH    3-Pn     H    1-AI-Pip(4) 2171  6-F    H  SO 2CH 2COOH    2-Hx     H    1-AI-Pip(4) 2172  6-F    H  SO 2CH 2COOH    3-Hx     H    1-AI-Pip(4) 2173  6-F    H  SO 2CH 2COOH    2-CF 3   H    1-AI-Pip(4) 2174  6-F    H  SO 2CH 2COOH    3-CF 3   H    1-AI-Pip(4) 2175  6-F    H  SO 2CH 2COOH    2-OMe    H    1-AI-Pip(4) 2176  6-F    H  SO 2CH 2COOH    3-OMe    H    1-AI-Pip(4) 2177  6-F    H  SO 2CH 2COOH    2-OEt    H    1-AI-Pip(4) 2178  6-F    H  SO 2CH 2COOH    3-OEt    H    1-AI-Pip(4) 2179  6-F    H  SO 2CH 2COOH    2-COOH   H    1-AI-Pip(4) 2180  6-F    H  SO 2CH 2COOH    3-COOH   H    1-AI-Pip(4) 2181  6-F    H  SO 2CH 2COOH    2-COOMe  H    1-AI-Pip(4) 2182 6-F    H  SO 2CH 2COOH    3-COOMe       H    1-AI-Pip(4) 2183 6-F    H  SO 2CH 2COOH    2-COOEt       H    1-AI-Pip(4) 2184 6-F    H  SO 2CH 2COOH    3-COOEt       H    1-AI-Pip(4) 2185 6-F    H  SO 2CH 2COOH    2-COOPr       H    1-AI-Pip(4) 2186 6-F    H  SO 2CH 2COOH    3-COOPr       H    1-AI-Pip(4) 2187 6-F    H  SO 2CH 2COOH    2-COOBu       H    1-AI-Pip(4) 2188 6-F    H  SO 2CH 2COOH    3-COOBu       H    1-AI-Pip(4) 2189 6-F    H  SO 2CH 2COOH    2-COOPn       H    1-AI-Pip(4) 2190 6-F    H  SO 2CH 2COOH    3-COOPn       H    1-AI-Pip(4) 2191 6-F    H  SO 2CH 2COOH    2-COOHx       H    1-AI-Pip(4) 2192 6-F    H  SO 2CH 2COOH    3-COOHx       H    1-AI-Pip(4) 2193 6-F    H  SO 2CH 2COOH    2-CONH 2      H    1-AI-Pip(4) 2194 6-F    H  SO 2CH 2COOH    3-CONH 2      H    1-AI-Pip(4) 2195 6-F    H  SO 2CH 2COOH    2-CONHMe      H    1-AI-Pip(4) 2196 6-F    H  SO 2CH 2COOH    3-CONHMe      H    1-AI-Pip(4) 2197 6-F    H  SO 2CH 2COOH    2-CONHEt      H    1-AI-Pip(4) 2198 6-F    H  SO 2CH 2COOH    3-CONHEt      H    1-AI-Pip(4) 2199 6-F    H  SO 2CH 2COOH    2-CON(Me) 2   H    1-AI-Pip(4) 2200 6-F    H  SO 2CH 2COOH    3-CON(Me) 2   H    1-AI-Pip(4) 2201 6-F    H  SO 2CH 2COOH    2-CON(Me)Et   H    1-AI-Pip(4) 2202 6-F    H  SO 2CH 2COOH    3-CON)(Me)Et  H    1-AI-Pip(4) 2203 6-F    H  SO 2CH 2COOH    2-CON(Et) 2   H    1-AI-Pip(4) 2204 6-F    H  SO 2CH 2COOH    3-CON(Et) 2   H    1-AI-Pip(4) 2205 2-Me   H  SO 2CH 2COOH    H             H    1-AI-Pip(4) 2206 3-Me   H  SO 2CH 2COOH    H             H    1-AI-Pip(4) 2207 4-Me   H  SO 2CH 2COOH    H             H    1-AI-Pip(4) 2208 5-Me   H  SO 2CH 2COOH    H             H    1-AI-Pip(4) 2209 5-Me   H  SO 2CH 2COOH    2-F           H    1-AI-Pip(4) 2210 5-Me   H  SO 2CH 2COOH    3-F           H    1-AI-Pip(4) 2211  5-Me  H  SO 2CH 2COOH    2-Cl       H    1-AI-Pip(4) 2212  5-Me  H  SO 2CH 2COOH    3-Cl       H    1-AI-Pip(4) 2213  5-Me  H  SO 2CH 2COOH    2-Br       H    1-AI-Pip(4) 2214  5-Me  H  SO 2CH 2COOH    3-Br       H    1-AI-Pip(4) 2215  5-Me  H  SO 2CH 2COOH    2-I        H    1-AI-Pip(4) 2216  5-Me  H  SO 2CH 2COOH    3-I        H    1-AI-Pip(4) 2217  5-Me  H  SO 2CH 2COOH    2-Me       H    1-AI-Pip(4) 2218  5-Me  H  SO 2CH 2COOH    3-Me       H    1-AI-Pip(4) 2219  5-Me  H  SO 2CH 2COOH    2-Et       H    1-AI-Pip(4) 2220  5-Me  H  SO 2CH 2COOH    3-Et       H    1-AI-Pip(4) 2221  5-Me  H  SO 2CH 2COOH    2-Pr       H    1-AI-Pip(4) 2222  5-Me  H  SO 2CH 2COOH    3-Pr       H    1-AI-Pip(4) 2223  5-Me  H  SO 2CH 2COOH    2-Bu       H    1-AI-Pip(4) 2224  5-Me  H  SO 2CH 2COOH    3-Bu       H    1-AI-Pip(4) 2225  5-Me  H  SO 2CH 2COOH    2-Pn       H    1-AI-Pip(4) 2226  5-Me  H  SO 2CH 2COOH    3-Pn       H    1-AI-Pip(4) 2227  5-Me  H  SO 2CH 2COOH    2-Hx       H    1-AI-Pip(4) 2228  5-Me  H  SO 2CH 2COOH    3-Hx       H    1-AI-Pip(4) 2229  5-Me  H  SO 2CH 2COOH    2-CF 3     H    1-AI-Pip(4) 2230  5-Me  H  SO 2CH 2COOH    3-CF 3     H    1-AI-Pip(4) 2231  5-Me  H  SO 2CH 2COOH    2-OMe      H    1-AI-Pip(4) 2232  5-Me  H  SO 2CH 2COOH    3-OMe      H    1-AI-Pip(4) 2233  5-Me  H  SO 2CH 2COOH    2-OEt      H    1-AI-Pip(4) 2234  5-Me  H  SO 2CH 2COOH    3-OEt      H    1-AI-Pip(4) 2235  5-Me  H  SO 2CH 2COOH    2-COOH     H    1-AI-Pip(4) 2236  5-Me  H  SO 2CH 2COOH    3-COOH     H    1-AI-Pip(4) 2237  5-Me  H  SO 2CH 2COOH    2-COOMe    H    1-AI-Pip(4) 2238  5-Me  H  SO 2CH 2COOH    3-COOMe    H    1-AI-Pip(4) 2239  5-Me  H  SO 2CH 2COOH    2-COOEt    H    1-AI-Pip(4) 2240  5-Me  H  SO 2CH 2COOH    3-COOEt       H    1-AI-Pip(4) 2241  5-Me  H  SO 2CH 2COOH    2-COOPr       H    1-AI-Pip(4) 2242  5-Me  H  SO 2CH 2COOH    3-COOPr       H    1-AI-Pip(4) 2243  5-Me  H  SO 2CH 2COOH    2-COOBu       H    1-AI-Pip(4) 2244  5-Me  H  SO 2CH 2COOH    3-COOBu       H    1-AI-Pip(4) 2245  5-Me  H  SO 2CH 2COOH    2-COOPn       H    1-AI-Pip(4) 2246  5-Me  H  SO 2CH 2COOH    3-COOPn       H    1-AI-Pip(4) 2247  5-Me  H  SO 2CH 2COOH    2-COOHx       H    1-AI-Pip(4) 2248  5-Me  H  SO 2CH 2COOH    3-COOHx       H    1-AI-Pip(4) 2249  5-Me  H  SO 2CH 2COOH    2-CONH 2      H    1-AI-Pip(4) 2250  5-Me  H  SO 2CH 2COOH    3-CONH 2      H    1-AI-Pip(4) 2251  5-Me  H  SO 2CH 2COOH    2-CONHMe      H    1-AI-Pip(4) 2252  5-Me  H  SO 2CH 2COOH    3-CONHMe      H    1-AI-Pip(4) 2253  5-Me  H  SO 2CH 2COOH    2-CONHEt      H    1-AI-Pip(4) 2254  5-Me  H  SO 2CH 2COOH    3-CONHEt      H    1-AI-Pip(4) 2255  5-Me  H  SO 2CH 2COOH    2-CON(Me) 2   H    1-AI-Pip(4) 2256  5-Me  H  SO 2CH 2COOH    3-CON(Me) 2   H    1-AI-Pip(4) 2257  5-Me  H  SO 2CH 2COOH    2-CON(Me)Et   H    1-AI-Pip(4) 2258  5-Me  H  SO 2CH 2COOH    3-CON(Me)Et   H    1-AI-Pip(4) 2259  5-Me  H  SO 2CH 2COOH    2-CON(Et) 2   H    1-AI-Pip(4) 2260  5-Me  H  SO 2CH 2COOH    3-CON(Et) 2   H    1-AI-Pip(4) 2261  6-Me  H  SO 2CH 2COOH    H             H    1-AI-Pip(4) 2262  6-OH  H  SO 2CH 2COOH    H             H    1-AI-Pip(4) 2263  6-OH  H  SO 2CH 2COOH    2-F           H    1-AI-Pip(4) 2264  6-OH  H  SO 2CH 2COOH    3-F           H    1-AI-Pip(4) 2265  6-OH  H  SO 2CH 2COOH    2-Cl          H    1-AI-Pip(4) 2266  6-OH  H  SO 2CH 2COOH    3-Cl          H    1-AI-Pip(4) 2267  6-OH  H  SO 2CH 2COOH    2-Br          H    1-AI-Pip(4) 2268  6-OH  H  SO 2CH 2COOH    3-Br          H    1-AI-Pip(4) 2269  6-OH  H  SO 2CH 2COOH   2-I      H   1-AI-Pip(4) 2270  6-OH  H  SO 2CH 2COOH   3-I      H   1-AI-Pip(4) 2271  6-OH  H  SO 2CH 2COOH   2-Me     H   1-AI-Pip(4) 2272  6-OH  H  SO 2CH 2COOH   3-Me     H   1-AI-Pip(4) 2273  6-OH  H  SO 2CH 2COOH   2-Et     H   1-AI-Pip(4) 2274  6-OH  H  SO 2CH 2COOH   3-Et     H   1-AI-Pip(4) 2275  6-OH  H  SO 2CH 2COOH   2-Pr     H   1-AI-Pip(4) 2276  6-OH  H  SO 2CH 2COOH   3-Pr     H   1-AI-Pip(4) 2277  6-OH  H  SO 2CH 2COOH   2-Bu     H   1-AI-Pip(4) 2278  6-OH  H  SO 2CH 2COOH   3-Bu     H   1-AI-Pip(4) 2279  6-OH  H  SO 2CH 2COOH   2-Pn     H   1-AI-Pip(4) 2280  6-OH  H  SO 2CH 2COOH   3-Pn     H   1-AI-Pip(4) 2281  6-OH  H  SO 2CH 2COOH   2-Hx     H   1-AI-Pip(4) 2282  6-OH  H  SO 2CH 2COOH   3-Hx     H   1-AI-Pip(4) 2283  6-OH  H  SO 2CH 2COOH   2-CF 3   H   1-AI-Pip(4) 2284  6-OH  H  SO 2CH 2COOH   3-CF 3   H   1-AI-Pip(4) 2285  6-OH  H  SO 2CH 2COOH   2-OMe    H   1-AI-Pip(4) 2286  6-OH  H  SO 2CH 2COOH   3-OMe    H   1-AI-Pip(4) 2287  6-OH  H  SO 2CH 2COOH   2-OEt    H   1-AI-Pip(4) 2288  6-OH  H  SO 2CH 2COOH   3-OEt    H   1-AI-Pip(4) 2289  6-OH  H  SO 2CH 2COOH   2-COOH   H   1-AI-Pip(4) 2290  6-OH  H  SO 2CH 2COOH   3-COOH   H   1-AI-Pip(4) 2291  6-OH  H  SO 2CH 2COOH   2-COOMe  H   1-AI-Pip(4) 2292  6-OH  H  SO 2CH 2COOH   3-COOMe  H   1-AI-Pip(4) 2293  6-OH  H  SO 2CH 2COOH   2-COOEt  H   1-AI-Pip(4) 2294  6-OH  H  SO 2CH 2COOH   3-COOEt  H   1-AI-Pip(4) 2295  6-OH  H  SO 2CH 2COOH   2-COOpr  H   1-AI-Pip(4) 2296  6-OH  H  SO 2CH 2COOH   3-COOPr  H   1-AI-Pip(4) 2297  6-OH  H  SO 2CH 2COOH   2-COOBu  H   1-AI-Pip(4) 2298  6-OH  H  SO 2CH 2COOH    3-COOBu       H      1-AI-Pip(4) 2299  6-OH  H  SO 2CH 2COOH    2-COOPn       H      1-AI-Pip(4) 2300  6-OH  H  SO 2CH 2COOH    3-COOPn       H      1-AI-Pip(4) 2301  6-OH  H  SO 2CH 2COOH    2-COOHx       H      1-AI-Pip(4) 2302  6-OH  H  SO 2CH 2COOH    3-COOHx       H      1-AI-Pip(4) 2303  6-OH  H  SO 2CH 2COOH    2-CONH 2      H      1-AI-Pip(4) 2304  6-OH  H  SO 2CH 2COOH    3-CONH 2      H      1-AI-Pip(4) 2305  6-OH  H  SO 2CH 2COOH    2-CONHMe      H      1-AI-Pip(4) 2306  6-OH  H  SO 2CH 2COOH    3-CONHMe      H      1-AI-Pip(4) 2307  6-OH  H  SO 2CH 2COOH    2-CONHEt      H      1-AI-Pip(4) 2308  6-OH  H  SO 2CH 2COOH    3-CONHEt      H      1-AI-Pip(4) 2309  6-OH  H  SO 2CH 2COOH    2-CON(Me) 2   H      1-AI-Pip(4) 2310  6-OH  H  SO 2CH 2COOH    3-CON(Me) 2   H      1-AI-Pip(4) 2311  6-OH  H  SO 2CH 2COOH    2-CON(Me)Et   H      1-AI-Pip(4) 2312  6-OH  H  SO 2CH 2COOH    3-CON(Me)Et   H      1-AI-Pip(4) 2313  6-OH  H  SO 2CH 2COOH    2-CON(Et) 2   H      1-AI-Pip(4) 2314  6-OH  H  SO 2CH 2COOH    3-CON(Et) 2   H      1-AI-Pip(4) 2315  6-OH  H  SO 2CH 2COOH    2-F           3-F    1-AI-Pip(4) 2316  6-OH  H  SO 2CH 2COOH    2-F           5-F    1-AI-Pip(4) 2317  6-OH  H  SO 2CH 2COOH    2-F           6-F    1-AI-Pip(4) 2318  6-OH  H  SO 2CH 2COOH    3-F           5-F    1-AI-Pip(4) 2319  6-OH  H  SO 2CH 2COOH    2-Cl          3-Cl   1-AI-Pip(4) 2320  6-OH  H  SO 2CH 2COOH    2-Cl          5-Cl   1-AI-Pip(4) 2321  6-OH  H  SO 2CH 2COOH    2-Cl          6-Cl   1-AI-Pip(4) 2322  6-OH  H  SO 2CH 2COOH    3-Cl          5-Cl   1-AI-Pip(4) 2323  6-OH  H  SO 2CH 2COOH    2-Me          3-Me   1-AI-Pip(4) 2324  6-OH  H  SO 2CH 2COOH    2-Me          5-Me   1-AI-Pip(4) 2325  6-OH  H  SO 2CH 2COOH    2-Me          6-Me   1-AI-Pip(4) 2326  6-OH  H  SO 2CH 2COOH    3-Me          5-Me   1-AI-Pip(4) 2327  6-OH  H  SO 2CH 2COOH      2-Cl       5-CONH 2   1-AI-Pip(4) 2328  6-OH  H  SO 2CH 2COOH      3-Cl       5-CONH 2   1-AI-Pip(4) 2329  6-OH  H  SO 2CH 2COOH      3-Cl       5-CONHMe   1-AI-Pip(4) 2330  6-OH  H  SO 2CH 2COOH      3-Cl       5-CONHEt   1-AI-Pip(4) 2331  6-OH  H  SO 2CH 2COOH      3-Cl       5-CONHPr   1-AI-Pip(4) 2332  6-OH  H  SO 2CH 2COOH      3-Cl       5-CONHBu   1-AI-Pip(4) 2333  6-OH  H  SO 2CH 2COOH      3-Cl       5-ONHpn    1-AI-Pip(4) 2334  6-OH  H  SO 2CH 2COOH      3-Cl       5-CONHx    1-AI-Pip(4) 2335  6-OH  H  SO 2CH 2COOH      2-Me       5-CONH 2   1-AI-Pip(4) 2336  6-OH  H  SO 2CH 2COOH      2-Me       5-CONHMe   1-AI-Pip(4) 2337  6-OH  H  SO 2CH 2COOH      2-Me       5-CONHEt   1-AI-Pip(4) 2338  6-OH  H  SO 2CH 2COOH      2-Me       5-CONHPr   1-AI-Pip(4) 2339  6-OH  H  SO 2CH 2COOH      2-Me       5-CONHBu   1-AI-Pip(4) 2340  6-OH  H  SO 2CH 2COOH      2-Me       5-CONHPn   1-AI-Pip(4) 2341  6-OH  H  SO 2CH 2COOH      2-Me       5-CONHHx   1-AI-Pip(4) 2342  6-OH  H  SO 2CH 2COOH      3-Me       5-CONH 2   1-AI-Pip(4) 2343  6-OH  H  SO 2CH 2COOH      3-Me       5-CONHMe   1-AI-Pip(4) 2344  6-OH  H  SO 2CH 2COOH      3-Me       5-CONHEt   1-AI-Pip(4) 2345  6-OH  H  SO 2CH 2COOH      3-Me       5-CONHPr   1-AI-Pip(4) 2346  6-OH  H  SO 2CH 2COOH      3-Me       5-CONHBu   1-AI-Pip(4) 2347  6-OH  H  SO 2CH 2COOH      3-Me       5-CONHPn   1-AI-Pip(4) 2348  6-OH  H  SO 2CH 2COOH      3-Me       5-CONHHx   1-AI-Pip(4) 2349  6-OH  H  SO 2CH 2COOH      2-CONH 2   6-CONH 2   1-AI-Pip(4) 2350  6-OH  H  SO 2CH 2COOH      3-CONH 2   5-CONH 2   1-AI-Pip(4) 2351  6-OH  H  SO 2CH 2COOH      3-CONHMe   5-CONHMe   1-AI-Pip(4)  2352  6-OH  H  SO 2CH 2COOH      3-CONHEt   5-CONHEt   1-AI-Pip(4) 2353  H     H  SO 2(CH 2) 2COOH  H          H          1-AI-Pip(4) 2354  H     H  SO 2(CH 2) 3COOH  H          H          1-AI-Pip(4) 2355  H     H  SO 2(CH 2) 4COOH  H          H          1-AI-Pip(4) 2356  H    H  SO 2(CH 2) 5COOH   H        H    1-AI-Pip(4) 2357  H    H  SO 2(CH 2) 6COOH   H        H    1-AI-Pip(4) 2358  H    H  SO 2CH 2COOMe      2-F      H    1-AI-Pip(4) 2359  H    H  SO 2CH 2COOMe      3-F      H    1-AI-Pip(4) 2360  H    H  SO 2CH 2COOMe      2-Cl     H    1-AI-Pip(4) 2361  H    H  SO 2CH 2COOMe      3-Cl     H    1-AI-Pip(4) 2362  H    H  SO 2CH 2COOMe      2-Br     H    1-AI-Pip(4) 2363  H    H  SO 2CH 2COOMe      3-Br     H    1-AI-Pip(4) 2364  H    H  SO 2CH 2COOMe      2-I      H    1-AI-Pip(4) 2365  H    H  SO 2CH 2COOMe      3-I      H    1-AI-Pip(4) 2366  H    H  SO 2CH 2COOMe      2-Me     H    1-AI-Pip(4) 2367  H    H  SO 2CH 2COOMe      3-Me     H    1-AI-Pip(4) 2368  H    H  SO 2CH 2COOMe      2-Et     H    1-AI-Pip(4) 2369  H    H  SO 2CH 2COOMe      3-Et     H    1-AI-Pip(4) 2370  H    H  SO 2CH 2COOMe      2-Pr     H    1-AI-Pip(4) 2371  H    H  SO 2CH 2COOMe      3-Pr     H    1-AI-Pip(4) 2372  H    H  SO 2CH 2COOMe      2- iPr  H    1-AI-Pip(4) 2373  H    H  SO 2CH 2COOMe      3- iPr  H    1-AI-Pip(4) 2374  H    H  SO 2CH 2COOMe      2-Bu     H    1-AI-Pip(4) 2375  H    H  SO 2CH 2COOMe      3-Bu     H    1-AI-Pip(4) 2376  H    H  SO 2CH 2COOMe      2- iBu  H    1-AI-Pip(4) 2377  H    H  SO 2CH 2COOMe      3- iBu  H    1-AI-Pip(4) 2378  H    H  SO 2CH 2COOMe      2- sBu  H    1-AI-Pip(4) 2379  H    H  SO 2CH 2COOMe      3- sBu  H    1-AI-Pip(4) 2380  H    H  SO 2CH 2COOMe      2- tBu  H    1-AI-Pip(4) 2381  H    H  SO 2CH 2COOMe      3- tBu  H    1-AI-Pip(4) 2382  H    H  SO 2CH 2COOMe      2-Pn     H    1-AI-Pip(4) 2383  H    H  SO 2CH 2COOMe      3-Pn     H    1-AI-Pip(4) 2384  H    H  SO 2CH 2COOMe      2-Hx     H    1-AI-Pip(4) 2385  H    H  SO 2CH 2COOMe    3-Hx          H    1-AI-Pip(4) 2386  H    H  SO 2CH 2COOMe    2-CF 3        H    1-AI-Pip(4) 2387  H    H  SO 2CH 2COOMe    3-CF 3        H    1-AI-Pip(4) 2388  H    H  SO 2CH 2COOMe    2-OMe         H    1-AI-Pip(4) 2389  H    H  SO 2CH 2COOMe    3-OMe         H    1-AI-Pip(4) 2390  H    H  SO 2CH 2COOMe    2-OEt         H    1-AI-Pip(4) 2391  H    H  SO 2CH 2COOMe    3-OEt         H    1-AI-Pip(4) 2392  H    H  SO 2CH 2COOMe    2-COOH        H    1-AI-Pip(4) 2393  H    H  SO 2CH 2COOMe    3-COOH        H    1-AI-Pip(4) 2394  H    H  SO 2CH 2COOMe    2-COOMe       H    1-AI-Pip(4) 2395  H    H  SO 2CH 2COOMe    3-COOMe       H    1-AI-Pip(4) 2396  H    H  SO 2CH 2COOMe    2-COOEt       H    1-AI-Pip(4) 2397  H    H  SO 2CH 2COOMe    3-COOEt       H    1-AI-Pip(4) 2398  H    H  SO 2CH 2COOMe    2-COOPr       H    1-AI-Pip(4) 2399  H    H  SO 2CH 2COOMe    3-COOPr       H    1-AI-Pip(4) 2400  H    H  SO 2CH 2COOMe    2-COOBu       H    1-AI-Pip(4) 2401  H    H  SO 2CH 2COOMe    3-COOBu       H    1-AI-Pip(4) 2402  H    H  SO 2CH 2COOMe    2-COOPn       H    1-AI-Pip(4) 2403  H    H  SO 2CH 2COOMe    3-COOPn       H    1-AI-Pip(4) 2404  H    H  SO 2CH 2COOMe    2-COOHx       H    1-AI-Pip(4) 2405  H    H  SO 2CH 2COOMe    3-COOHx       H    1-AI-Pip(4) 2406  H    H  SO 2CH 2COOMe    2-CONH 2      H    1-AI-Pip(4) 2407  H    H  SO 2CH 2COOMe    3-CONH 2      H    1-AI-Pip(4) 2408  H    H  SO 2CH 2COOMe    2-CONHMe      H    1-AI-Pip(4) 2409  H    H  SO 2CH 2COOMe    3-CONHMe      H    1-AI-Pip(4) 2410  H    H  SO 2CH 2COOMe    2-COHHEt      H    1-AI-Pip(4) 2411  H    H  SO 2CH 2COOMe    3-CONHEt      H    1-AI-Pip(4) 2412  H    H  SO 2CH 2COOMe    2-CON(Me) 2   H    1-AI-Pip(4) 2413  H    H  SO 2CH 2COOMe    3-CON(Me) 2   H    1-AI-Pip(4) 2414  H    H  SO 2CH 2COOMe    2-CON(Me)Et   H           1-AI-Pip(4) 2415  H    H  SO 2CH 2COOMe    3-CON(Me)Et   H           1-AI-Pip(4) 2416  H    H  SO 2CH 2COOMe    2-CON(Et) 2   H           1-AI-Pip(4) 2417  H    H  SO 2CH 2COOMe    3-CON(Et) 2   H           1-AI-Pip(4) 2418  H    H  SO 2CH 2COOMe    2-F           3-F         1-AI-Pip(4) 2419  H    H  SO 2CH 2COOMe    2-F           5-F         1-AI-Pip(4) 2420  H    H  SO 2CH 2COOMe    2-F           6-F         1-AI-Pip(4) 2421  H    H  SO 2CH 2COOMe    3-F           5-F         1-AI-Pip(4) 2422  H    H  SO 2CH 2COOMe    2-Cl          3-Cl        1-AI-Pip(4) 2423  H    H  SO 2CH 2COOMe    2-Cl          5-Cl        1-AI-Pip(4) 2424  H    H  SO 2CH 2COOMe    2-Cl          6-Cl        1-AI-Pip(4) 2425  H    H  SO 2CH 2COOMe    3-Cl          5-Cl        1-AI-Pip(4) 2426  H    H  SO 2CH 2COOMe    2-Me          3-Me        1-AI-Pip(4) 2427  H    H  SO 2CH 2COOMe    2-Me          5-Me        1-AI-Pip(4) 2428  H    H  SO 2CH 2COOMe    2-Me          6-Me        1-AI-Pip(4) 2429  H    H  SO 2CH 2COOMe    3-Me          5-Me        1-AI-Pip(4) 2430  H    H  SO 2CH 2COOMe    2-Cl          5-CONH 2    1-AI-Pip(4) 2431  H    H  SO 2CH 2COOMe    3-Cl          5-CONH 2    1-AI-Pip(4) 2432  H    H  SO 2CH 2COOMe    3-Cl          5-CONHMe    1-AI-Pip(4) 2433  H    H  SO 2CH 2COOMe    3-Cl          5-CONHEt    1-AI-Pip(4) 2434  H    H  SO 2CH 2COOMe    3-Cl          5-CONHPr    1-AI-Pip(4) 2435  H    H  SO 2CH 2COOMe    3-Cl          5-CONHBu    1-AI-Pip(4) 2436  H    H  SO 2CH 2COOMe    3-Cl          5-CONHPn    1-AI-Pip(4) 2437  H    H  SO 2CH 2COOMe    3-Cl          5-CONHHx    1-AI-Pip(4) 2438  H    H  SO 2CH 2COOMe    2-Me          5-CONH 2    1-AI-Pip(4) 2439  H    H  SO 2CH 2COOMe    2-Me          5-CONHMe    1-AI-Pip(4) 2440  H    H  SO 2CH 2COOMe    2-Me          5-CONHEt    1-AI-Pip(4) 2441  H    H  SO 2CH 2COOMe    2-Me          5-CONHPr    1-AI-Pip(4) 2442  H    H  SO 2CH 2COOMe    2-Me          5-CONHBu    1-AI-Pip(4) 2443  H     H  SO 2CH 2COOMe    2-Me        5-CONHPn   1-AI-Pip(4) 2444  H     H  SO 2CH 2COOMe    2-Me        5-CONHHx   1-AI-Pip(4) 2445  H     H  SO 2CH 2COOMe    3-Me        5-CONH 2   1-AI-Pip(4) 2446  H     H  SO 2CH 2COOMe    3-Me        5-CONHMe   1-AI-Pip(4) 2447  H     H  SO 2CH 2COOMe    3-Me        5-CONHEt   1-AI-Pip(4) 2448  H     H  SO 2CH 2COOMe    3-Me        5-CONHPr   1-AI-Pip(4) 2449  H     H  SO 2CH 2COOMe    3-Me        5-CONHBu   1-AI-Pip(4) 2450  H     H  SO 2CH 2COOMe    3-Me        5-CONHP    1-AI-Pip(4) 2451  H     H  SO 2CH 2COOMe    3-Me        5-CONHHx   1-AI-Pip(4) 2452  H     H  SO 2CH 2COOMe    2-CONH 2    6-CONH 2   1-AI-Pip(4) 2453  H     H  SO 2CH 2COOMe    3-CONH 2    5-CONH 2   1-AI-Pip(4) 2454  H     H  SO 2CH 2COOMe    3-CONHMe    5-CONHMe   1-AI-Pip(4) 2455  H     H  SO 2CH 2COOMe    3-CONHEt    5-CONHEt   1-AI-Pip(4) 2456  6-OH  H  SO 2CH 2COOMe    2-F         H          1-AI-Pip(4) 2457  6-OH  H  SO 2CH 2COOMe    3-F         H          1-AI-Pip(4) 2458  6-OH  H  SO 2CH 2COOMe    2-Cl        H          1-AI-Pip(4) 2459  6-OH  H  SO 2CH 2COOMe    3-Cl        H          1-AI-Pip(4) 2460  6-OH  H  SO 2CH 2COOMe    2-Br        H          1-AI-Pip(4) 246 1 6-OH  H  SO 2CH 2COOMe    3-Br        H          1-AI-Pip(4) 2462  6-OH  H  SO 2CH 2COOMe    2-I         H          1-AI-Pip(4) 2463  6-OH  H  SO 2CH 2COOMe    3-I         H          1-AI-Pip(4) 2464  6-OH  H  SO 2CH 2COOMe    2-Me        H          1-AI-Pip(4) 2465  6-OH  H  SO 2CH 2COOMe    3-Me        H          1-AI-Pip(4) 2466  6-OH  H  SO 2CH 2COOMe    2-Et        H          1-AI-Pip(4) 2467  6-OH  H  SO 2CH 2COOMe    3-Et        H          1-AI-Pip(4) 2468  6-OH  H  SO 2CH 2COOMe    2-Pr        H          1-AI-Pip(4) 2469  6-OH  H  SO 2CH 2COOMe    3-Pr        H          1-AI-Pip(4) 2470  6-OH  H  SO 2CH 2COOMe    2- iPr     H          1-AI-Pip(4) 2471  6-OH  H  SO 2CH 2COOMe    3- iPr     H          1-AI-Pip(4) 2472  6-OH   H  SO 2CH 2COOMe    2-Bu       H    1-AI-Pip(4) 2473  6-OH   H  SO 2CH 2COOMe    3-Bu       H    1-AI-Pip(4) 2474  6-OH   H  SO 2CH 2COOMe    2- iBu    H    1-AI-Pip(4) 2475  6-OH   H  SO 2CH 2COOMe    3- iBu    H    1-AI-Pip(4) 2476  6-OH   H  SO 2CH 2COOMe    2- sBu    H    1-AI-Pip(4) 2477  6-OH   H  SO 2CH 2COOMe    3- sBu    H    1-AI-Pip(4) 2478  6-OH   H  SO 2CH 2COOMe    2- tBu    H    1-AI-Pip(4) 2479  6-OH   H  SO 2CH 2COOMe    3- tBu    H    1-AI-Pip(4) 2480  6-OH   H  SO 2CH 2COOMe    2-Pn       H    1-AI-Pip(4) 2481  6-OH   H  SO 2CH 2COOMe    3-Pn       H    1-AI-Pip(4) 2482  6-OH   H  SO 2CH 2COOMe    2-Hx       H    1-AI-Pip(4) 2483  6-OH   H  SO 2CH 2COOMe    3-Hx       H    1-AI-Pip(4) 2484  6-OH   H  SO 2CH 2COOMe    2-CF 3     H    1-AI-Pip(4) 2485  6-OH   H  SO 2CH 2COOMe    3-CF 3     H    1-AI-Pip(4) 2486  6-OH   H  SO 2CH 2COOMe    2-OMe      H    1-AI-Pip(4) 2487  6-OH   H  SO 2CH 2COOMe    3-OMe      H    1-AI-Pip(4) 2488  6-OH   H  SO 2CH 2COOMe    2-OEt      H    1-AI-Pip(4) 2489  6-OH   H  SO 2CH 2COOMe    3-OEt      H    1-AI-Pip(4) 2490  6-OH   H  SO 2CH 2COOMe    2-COOH     H    1-AI-Pip(4) 2491  6-OH   H  SO 2CH 2COOMe    3-COOH     H    1-AI-Pip(4) 2492  6-OH   H  SO 2CH 2COOMe    2-COOMe    H    1-AI-Pip(4) 2493  6-OH   H  SO 2CH 2COOMe    3-COOMe    H    1-AI-Pip(4) 2494  6-OH   H  SO 2CH 2COOMe    2-COOEt    H    1-AI-Pip(4) 2495  6-OH   H  SO 2CH 2COOMe    3-COOEt    H    1-AI-Pip(4) 2496  6-OH   H  SO 2CH 2COOMe    2-COOPr    H    1-AI-Pip(4) 2497  6-OH   H  SO 2CH 2COOMe    3-COOPr    H    1-AI-Pip(4) 2498  6-OH   H  SO 2CH 2COOMe    2-COOBu    H    1-AI-Pip(4) 2499  6-OH   H  SO 2CH 2COOMe    3-COOBu    H    1-AI-Pip(4) 2500  6-OH   H  SO 2CH 2COOMe    2-COOPn    H    1-AI-Pip(4) 2501  6-OH  H  SO 2CH 2COOMe    3-COOPn       H         1-AI-Pip(4) 2502  6-OH  H  SO 2CH 2COOMe    2-COOHx       H         1-AI-Pip(4) 2503  6-OH  H  SO 2CH 2COOMe    3-COOHx       H         1-AI-Pip(4) 2504  6-OH  H  SO 2CH 2COOMe    2-CONH 2      H         1-AI-Pip(4) 2505  6-OH  H  SO 2CH 2COOMe    3-CONH 2      H         1-AI-Pip(4) 2506  6-OH  H  SO 2CH 2COOMe    2-ONHMe       H         1-AI-Pip(4) 2507  6-OH  H  SO 2CH 2COOMe    3-CONHMe      H         1-AI-Pip(4) 2508  6-OH  H  SO 2CH 2COOMe    2-CONHEt      H         1-AI-Pip(4) 2509  6-OH  H  SO 2CH 2COOMe    3-CONHEt      H         1-AI-Pip(4) 2510  6-OH  H  SO 2CH 2COOMe    2-CON(Me) 2   H         1-AI-Pip(4) 2511  6-OH  H  SO 2CH 2COOMe    3-CON(Me) 2   H         1-AI-Pip(4) 2512  6-OH  H  SO 2CH 2COOMe    2-CON(Me)Et   H         1-AI-Pip(4) 2513  6-OH  H  SO 2CH 2COOMe    3-CON(Me)Et   H         1-AI-Pip(4) 2514  6-OH  H  SO 2CH 2COOMe    2-CON(Et) 2   H         1-AI-Pip(4) 2515  6-OH  H  SO 2CH 2COOMe    3-CON(Et) 2   H         1-AI-Pip(4) 2516  6-OH  H  SO 2CH 2COOMe    2-F           3-F       1-AI-Pip(4) 2517  6-OH  H  SO 2CH 2COOMe    2-F           5-F       1-AI-Pip(4) 2518  6-OH  H  SO 2CH 2COOMe    2-F           6-F       1-AI-Pip(4) 2519  6-OH  H  SO 2CH 2COOMe    3-F           5-F       1-AI-Pip(4) 2520  6-OH  H  SO 2CH 2COOMe    2-Cl          3-Cl      1-AI-Pip(4) 2521  6-OH  H  SO 2CH 2COOMe    2-Cl          5-Cl      1-AI-Pip(4) 2522  6-OH  H  SO 2CH 2COOMe    2-Cl          6-Cl      1-AI-Pip(4) 2523  6-OH  H  SO 2CH 2COOMe    3-Cl          5-Cl      1-AI-Pip(4) 2524  6-OH  H  SO 2CH 2COOMe    2-Me          3-Me      1-AI-Pip(4) 2525  6-OH  H  SO 2CH 2COOMe    2-Me          5-Me      1-AI-Pip(4) 2526  6-OH  H  SO 2CH 2COOMe    2-Me          6-Me      1-AI-Pip(4) 2527  6-OH  H  SO 2CH 2COOMe    3-Me          5-Me      1-AI-Pip(4) 2528  6-OH  H  SO 2CH 2COOMe    2-Cl          5-CONH 2  1-AI-Pip(4) 2529  6-OH  H  SO 2CH 2COOMe    3-Cl          5-CONH 2  1-AI-Pip(4) 2530  6-OH  H  SO 2CH 2COOMe    3-Cl       5-CONHMe  1-AI-Pip(4) 2531  6-OH  H  SO 2CH 2COOMe    3-Cl       5-CONHEt  1-AI-Pip(4) 2532  6-OH  H  SO 2CH 2COOMe    3-Cl       5-CONHPr  1-AI-Pip(4) 2533  6-OH  H  SO 2CH 2COOMe    3-Cl       5-CONHBu  1-AI-Pip(4) 2534  6-OH  H  SO 2CH 2COOMe    3-Cl       5-CONHPn  1-AI-Pip(4) 2535  6-OH  H  SO 2CH 2COOMe    3-Cl       5-CONHHx  1-AI-Pip(4) 2536  6-OH  H  SO 2CH 2COOMe    2-Me       5-CONH 2  1-AI-Pip(4) 2537  6-OH  H  SO 2CH 2COOMe    2-Me       5-CONHMe  1-AI-Pip(4) 2538  6-OH  H  SO 2CH 2COOMe    2-Me       5-CONHEt  1-AI-Pip(4) 2539  6-OH  H  SO 2CH 2COOMe    2-Me       5-CONHPr  1-AI-Pip(4) 2540  6-OH  H  SO 2CH 2COOMe    2-Me       5-CONHBu  1-AI-Pip(4) 2541  6-OH  H  SO 2CH 2COOMe    2-Me       5-CONHPn  1-AI-Pip(4) 2542  6-OH  H  SO 2CH 2COOMe    2-Me       5-CONHHx  1-AI-Pip(4) 2543  6-OH  H  SO 2CH 2COOMe    3-Me       5-CONH 2  1-AI-Pip(4) 2544  6-OH  H  SO 2CH 2COOMe    3-Me       5-CONHMe  1-AI-Pip(4) 2545  6-OH  H  SO 2CH 2COOMe    3-Me       5-CONHEt  1-AI-Pip(4) 2546  6-OH  H  SO 2CH 2COOMe    3-Me       5-CONHPr  1-AI-Pip(4) 2547  6-OH  H  SO 2CH 2COOMe    3-Me       5-CONHBu  1-AI-Pip(4) 2548  6-OH  H  SO 2CH 2COOMe    3-Me       5-CONHPn  1-AI-Pip(4) 2549  6-OH  H  SO 2CH 2COOMe    3-Me       5-CONHHx  1-AI-Pip(4) 255O  6-OH  H  SO 2CH 2COOMe    2-CONH 2   6-CONH 2  1-AI-Pip(4) 2551  6-OH  H  SO 2CH 2COOMe    3-CONH 2   5-CONH 2  1-AI-Pip(4) 2552  6-OH  H  SO 2CH 2COOMe    3-CONHMe   5-CONHMe  1-AI-Pip(4) 2553  6-OH  H  SO 2CH 2COOMe    3-CONHEt   5-CONHEt  1-AI-Pip(4)
In the benzamidine derivative shown in the general formula of the present invention (I), can enumerate following exemplary compounds number as preferred compound: 83,90,93,101,137,140,142,148,177,237,297,358,478,542,663,668,788,849,864,948,1O14,1080,1220,1280,1408,1410,1411,1412,1413,1414,1415,1416,1419,1420,1422,1424,1426,1434,1440,1442,1448,1450,1460,1462,1466,1474,1478,1482,1484,1492,1498,1509,1513,1539,1638,1711,1771,1839,1843,1849,1881,1939,1941,1943,1945,1949,1951,1955,1963,1969,1971,1975,1977,1979,1989,1991,1995,2003,2007,2011,2013,2027,2038,2040,2042,2044,2048,2054,2068,2070,2076,2078,2088,2094,2109,2208,2262,2266,2272,2304 or 2353.
Preferred compound can be enumerated following exemplary compounds number: 90,137,177,237,297,358,478,542,663,668,788,849,864,948,1014,1080,1408,1410,1412,1414,1416,1419,1420,1426,1440,1442,1450,1460,1462,1466,1474,1478,1482,1484,1492,1498,1509,1513,1638,1711,1771,1839,1843,1849,1881,1939,1941,1943,1945,1949,1951,1955,1969,1971,1975,1979,1989,1991,1995,2003,2007,2011,2013,2027,2038,2040,2042,2094,2208,2262,2266,2272 or 2304.
Preferred compound can be enumerated following exemplary compounds number again: 668,849,1014,1410,1412,1414,1420,1426,1440,1442,1450,1460,1462,1466,1474,1478,1482,1484,1498,1509,1839,1843,1939,1941,1943,1945,1949,1955,1969,1971,1975,1979,1989,1991,1995,2003,2007,2011,2013,2027 or 2038.
Particularly preferred compound can be enumerated:
Exemplary compounds 1410:N-(4-(1-acetimidoyl piperidin-4-yl oxygen) phenyl)-N-(3-(3-carbamimido-phenyl)-2-(E) propenyl) sulphonamide ethyl acetate,
Exemplary compounds 1414:N-(4-(1-acetimidoyl piperidin-4-yl oxygen)-3-chloro-phenyl-)-N-(3-(3-carbamimido-phenyl)-2-(E) propenyl) sulphonamide ethyl acetate,
Exemplary compounds 1420:N-(4-(1-acetimidoyl piperidin-4-yl oxygen)-3-aminomethyl phenyl)-N-(3-(3-carbamimido-phenyl)-2-(E) propenyl) sulphonamide ethyl acetate,
Exemplary compounds 1460:N-(4-(1-acetimidoyl piperidin-4-yl oxygen)-3-formamyl phenyl)-N-(3-(3-carbamimido-phenyl)-2-(E) propenyl) sulphonamide ethyl acetate,
Exemplary compounds 1939:N-(4-(1-acetimidoyl piperidin-4-yl oxygen) phenyl)-N-(3-(3-carbamimido-phenyl)-2-(E) propenyl) sulphonamide acetic acid,
Exemplary compounds 1941:N-(4-(1-acetimidoyl piperidin-4-yl oxygen)-3-fluorophenyl)-N-(3-(3-carbamimido-phenyl)-2-(E) propenyl) sulphonamide acetic acid,
Exemplary compounds 1943:N-(4-(1-acetimidoyl piperidin-4-yl oxygen)-3-chloro-phenyl-)-N-(3-(3-carbamimido-phenyl)-2-(E) propenyl) sulphonamide acetic acid,
Exemplary compounds 1949:N-(4-(1-acetimidoyl piperidin-4-yl oxygen)-3-aminomethyl phenyl)-N-(3-(3-carbamimido-phenyl)-2-(E) propenyl) sulphonamide acetic acid,
Exemplary compounds 1969:N-(4-(1-acetimidoyl piperidin-4-yl oxygen)-3-trifluoromethyl)-N-(3-(3-carbamimido-phenyl)-2-(E) propenyl) sulphonamide acetic acid,
Exemplary compounds 1989:N-(4-(1-acetimidoyl piperidin-4-yl oxygen)-3-formamyl phenyl)-N-(3-(3-carbamimido-phenyl)-2-(E) propenyl) sulphonamide acetic acid,
Exemplary compounds 2003:N-(4-(1-acetimidoyl piperidin-4-yl oxygen)-3,5-dichlorophenyl)-N-(3-(3-carbamimido-phenyl)-2-(E) propenyl) sulphonamide ethyl acetate,
Exemplary compounds 2007:N-(4-(1-acetimidoyl piperidin-4-yl oxygen)-3,5-dichlorophenyl)-N-(3-(3-carbamimido-phenyl)-2-(E) propenyl) sulphonamide acetic acid, or
Exemplary compounds 2038:N-(4-(1-acetimidoyl piperidin-4-yl oxygen)-N-(3-(3-carbamimido-phenyl)-2-fluoro-2-(E)-propenyl) sulphonamide acetic acid.
Formula of the present invention (I) compound can easily be made by the following method.(method A) (method B) (method C) (method D)
Figure A0081780001191
In above-mentioned reaction scheme:
R 1, R 2, R 3, R 4, R 5And R 6By aforementioned definitions;
R 3A represents hydrogen atom;
R 3B represents C 1-C 6Alkyl; By shielded hydroxyl or (C 1-C 6Alkoxyl group) C of carbonyl substituted 1-C 6Alkyl; Group shown in the general formula (II)
Figure A0081780001201
In the formula, R 7, m and n be by aforementioned definitions; C 7-C 15Aralkyl; C 1-C 6Alkyl sulphonyl; Or by (C 1-C 6Alkoxyl group) C of carbonyl substituted 1-C 6Alkyl sulphonyl;
R 3C represents C 1-C 6Alkyl or C 7-C 15Aralkyl;
R 3D represents C 1-C 6Alkanoyl or the C that is replaced by shielded hydroxyl 2-C 6Alkanoyl;
R 8With R 6Identical, but amino is protected;
R 9Represent C 1-C 5Alkyl, C 6-C 14Aryl or C 7-C 14Aralkyl;
R 10Represent C 1-C 6Alkanoyl; Or the C that is replaced by shielded hydroxyl 2-C 6Alkanoyl;
R 11Represent C 1-C 6Alkyl;
R 12The representation hydroxy protecting group;
R 13With R 1Identical, but hydroxyl is protected;
X represents halogen atom.
At above-mentioned R 3" C in the b definition 1-C 6Alkyl ", " by (C 1-C 6Alkoxyl group) C of carbonyl substituted 1-C 6Alkyl ", " group shown in the general formula (II)
Figure A0081780001202
R in the formula 7, m and n be by aforementioned definitions ", " C 7-C 15Aralkyl ", " C 1-C 6Alkyl sulphonyl " and " by (C 1-C 6Alkoxyl group) C of carbonyl substituted 1-C 6Alkyl sulfonyl "; R 3" C in the c definition 1-C 6Alkyl " and " C 7-C 15Aralkyl "; And R 3" C in the d definition 1-C 6Alkanoyl " implication and above-mentioned R 3Middle definition identical.
At above-mentioned R 3" the C that is replaced by shielded hydroxyl in the b definition 1-C 6Alkyl " implication and R 3Middle definition identical, but hydroxyl is protected.
At above-mentioned R 3" the C that is replaced by shielded hydroxyl in the d definition 1-C 6Alkanoyl " implication and R 3" the hydroxyl C of middle definition 2-C 6Alkanoyl " identical, but hydroxyl is protected.
Above-mentioned R 3" the C that is replaced by shielded hydroxyl in the b definition 1-C 6Alkyl " in " hydroxyl protecting group ", R 3D and R 10" the C that is replaced by shielded hydroxyl in the definition 2-C 6Alkanoyl " in " hydroxyl protecting group ", R 12" hydroxyl protecting group " and R in the definition 13Middle " hydroxyl protecting group " that comprises has no particular limits, just can as long as usually can use as hydroxyl protecting group, its example comprises for example alkanoyl, such as formyl radical, ethanoyl, propionyl, butyryl radicals, isobutyryl, pentanoyl, valeryl, pentanoyl, isovaleryl, capryloyl, nonanoyl, decanoyl, 3-methyl nonanoyl, 8-methyl nonanoyl, 3-ethyl capryloyl, 3,7-dimethyl-octa acyl group, undecanoyl, lauroyl, tridecanoyl, tetradecanoyl, pentadecanoyl, hexadecanoyl, 1-methyl pentadecanoyl, 14-methyl pentadecanoyl, 13,13-dimethyl tetradecanoyl, the heptadecane acyl group, 15-methyl hexadecanoyl, octadecanoyl, 1-methyl heptadecane acyl group, the nonadecane acyl group, eicosane acyl group or heneicosane acyl group; The carboxyl alkanoyl is such as mono succinate acyl group, glutaryl or hexanodioic acid monoacyl; The halogenated alkane acyl group is such as chloracetyl, dichloro-acetyl, tribromo-acetyl base or trifluoroacetyl group; The oxyalkyl chain alkyloyl is such as the methoxyl group ethanoyl; The unsaturated chain alkyloyl is such as (E)-2-methyl-2-butene acyl group; Aryl carbonyl is such as benzoyl, α-naphthoyl or β-naphthoyl; The halogenated aryl carbonyl is such as 2-benzoyl bromide or 4-chlorobenzene formacyl; The alkylated aryl carbonyl is such as 2,4,6-trimethylbenzoyl or 4-methyl benzoyl; The alkoxylate aryl carbonyl is such as the 4-anisoyl; Carboxylated aryl carbonyl is such as 2-carboxylbenzoyl, 3-carboxylbenzoyl or 4-carboxylbenzoyl; The nitration aryl carbonyl is such as 4-nitro benzoyl or 2-nitro benzoyl; The earbalkoxylation aryl carbonyl is such as 2-(methoxycarbonyl) benzoyl; The arylation aryl carbonyl is such as 4-phenyl benzoyl; THP trtrahydropyranyl or tetrahydro thiapyran base are such as tetrahydropyrans-2-base, 3-bromine tetrahydropyrans-2-base, 4-methoxyl group tetrahydropyran-4-base, tetrahydric thiapyran-2-base or 4-methoxyl group tetrahydric thiapyran-4-group; Tetrahydrofuran base or tetrahydro-thienyl are such as tetrahydrofuran (THF)-2-base or tetramethylene sulfide-2-base; Alkoxy methyl, such as methoxymethyl, 1,1-dimethyl-1-methoxymethyl, ethoxyl methyl, propoxy-methyl, isopropoxy methyl, butoxymethyl or tert.-butoxy methyl; The alkoxylate alkoxy methyl is such as 2-methoxy ethoxy methyl; The haloalkoxy ylmethyl is such as 2,2,2-trichlorine ethoxyl methyl or two (2-chloroethoxy) methyl; The alkoxylate ethyl is such as 1-ethoxyethyl group or 1-(isopropoxy) ethyl; Halogenated ethyl is such as 2,2,2-, three chloroethyls; By the aralkyl of 1-3 aryl replacement, such as benzyl, α-menaphthyl, β-menaphthyl, diphenyl-methyl, trityl, Alpha-Naphthyl diphenyl-methyl or 9-anthracene methyl; The aralkyl that aromatic ring has been replaced by alkyl, alkoxyl group, halogen or cyano group, such as 4-methyl-benzyl, 2,4,6-trimethyl benzyl, 3,4,5-trimethyl benzyl, 4-methoxy-benzyl, 4-p-methoxy-phenyl diphenyl methyl, 2-nitrobenzyl, 4-nitrobenzyl, 4-chlorobenzyl, 4-bromobenzyl or 4-cyano group benzyl; Carbalkoxy is such as methoxycarbonyl, ethoxycarbonyl, tertbutyloxycarbonyl or isobutyl boc; The haloalkoxy carbonyl is such as 2,2,2-trichloro-ethoxycarbonyl; Chain ene keto carbonyl is such as ethylene oxy carbonyl or allyloxycarbonyl; Aromatic ring is randomly by the aralkoxycarbonyl of 1 or 2 alkoxyl group or nitro replacement, such as carbobenzoxy-(Cbz), 4-methoxyl group benzyloxy carbonyl, 3,4-dimethoxy-benzyloxycarbonyl, 2-nitro carbobenzoxy-(Cbz) or 4-nitro carbobenzoxy-(Cbz); Or silyl, such as trimethyl silyl, triethylsilyl, sec.-propyl dimetylsilyl, t-butyldimethylsilyl, methyl di-isopropyl silyl, methyl di-t-butyl silyl, triisopropyl silyl, diphenyl methyl silyl, phenylbenzene butyl silyl, phenylbenzene sec.-propyl silyl or phenyl di-isopropyl silyl.
R 3" the C that is replaced by shielded hydroxyl in the b definition 1-C 6Alkyl " in " hydroxyl protecting group ", R 3D and R 10" the C that is replaced by shielded hydroxyl in the definition 2-C 6Alkanoyl " in " hydroxyl protecting group " alkanoyl class preferably, particularly preferably be ethanoyl.On the other hand, R 12" hydroxyl protecting group " and R in the definition 13Middle " hydroxyl protecting group " that comprises be the alkoxide alkoxy methyl preferably, particularly preferably is methoxymethyl.
Above-mentioned R 8" amino protecting group " in the definition is not particularly limited, if usually can as amino protecting group just use can, its example comprises for example C 1-C 6Alkanoyl is such as formyl radical, ethanoyl, propionyl, butyryl radicals, isobutyryl, pentanoyl, valeryl, pentanoyl, isovaleryl or caproyl; By halogen or C 1-C 4The C that alkoxyl group replaces 1-C 4Alkanoyl, such as chloracetyl, dichloro-acetyl, tribromo-acetyl base, trifluoroacetyl group, 3-fluorine propionyl, 4,4-two chlorobutyryls, methoxy ethanoyl, fourth oxygen ethanoyl, ethoxy propionyl or the third oxygen butyryl radicals; Unsaturated C 1-C 4Alkanoyl is such as acryl, propioloyl, methacryloyl, crotonyl or isocrotonoyl; Optionally by halogen, C 1-C 4Alkyl, C 1-C 4Alkoxyl group, C 1-C 4Carbalkoxy, C 6-C 10The C that aryl or nitro replace 6-C 10Aryl carbonyl, such as benzoyl, α-naphthoyl, β-naphthoyl, the 2-fluoro benzoyl, the 2-benzoyl bromide, 2,4-dichloro-benzoyl base, 6-chloro-α-naphthoyl, the 4-methyl benzoyl, 4-propylbenzene formyl radical, 4-tert.-butylbenzene formyl radical, 2,4,6-trimethylbenzoyl, 6-ethyl-α-naphthoyl, the 4-anisoyl, 4-propoxy-benzoyl, 4-tert.-butoxy benzoyl, 6-oxyethyl group-α-naphthoyl, 2-ethoxycarbonyl benzoyl, 4-tertbutyloxycarbonyl benzoyl, 6-methoxycarbonyl-α-naphthoyl, 4-phenyl benzoyl, 4-phenyl-α-naphthoyl, 6-Alpha-Naphthyl benzoyl, the 4-nitro benzoyl, 2-nitro benzoyl or 6-nitro-α-naphthoyl; Optionally by halogen atom or three (C 1-C 4) C that replaces of alkyl silyl 1-C 4Carbalkoxy, such as methoxycarbonyl, ethoxycarbonyl, the third oxygen carbonyl, isopropyl oxygen carbonyl, butoxy carbonyl, isobutyl boc, secondary butoxy carbonyl, tertbutyloxycarbonyl, chloromethane oxygen carbonyl, 2,2,2-trichloro-ethoxycarbonyl, 2-fluorine the third oxygen carbonyl, 2-bromine tertbutyloxycarbonyl, 2,2-dibromo tertbutyloxycarbonyl, triethylsilyl methoxycarbonyl, 2-trimethyl silyl ethoxycarbonyl, 4-tripropyl silyl butoxy carbonyl or t-butyldimethylsilyl the third oxygen carbonyl; C 2-C 5Chain ene keto carbonyl is such as ethylene oxy carbonyl, allyloxycarbonyl, 1,3-butadiene base oxygen carbonyl or 2-amylene oxygen carbonyl; The aryl dicarbapentaborane is such as the phenyl-diformyl base; Aralkyl is such as benzyl, styroyl, 3-phenyl propyl, 4-phenyl butyl, α-menaphthyl, β-menaphthyl, diphenyl-methyl, trityl, Alpha-Naphthyl diphenyl-methyl or 9-anthracene methyl; Or optionally by the C of methoxyl group or nitro replacement 7-C 15Aralkoxycarbonyl is such as carbobenzoxy-(Cbz), (1-phenyl) carbobenzoxy-(Cbz), Alpha-Naphthyl methoxycarbonyl, betanaphthyl methoxycarbonyl, 9-anthryl methoxycarbonyl, to methoxyl group benzyloxy carbonyl or to the nitrobenzyl carbonyl.
R 8Preferred amino protecting group is C in the definition 1-C 4Alkanoyl, trifluoroacetyl group, methoxy ethanoyl, benzoyl, α-naphthoyl, β-naphthoyl, anisoyl, nitro benzoyl, C 1-C 4Carbalkoxy, 2; 2; 2-trichloro-ethoxycarbonyl, triethylsilyl methoxycarbonyl, 2-trimethyl silyl ethoxycarbonyl, ethylene oxy carbonyl, allyloxycarbonyl, phenyl-diformyl base, benzyl, carbobenzoxy-(Cbz) or nitro carbobenzoxy-(Cbz); more preferably formyl radical, ethanoyl, benzoyl, 4-anisoyl, 4-nitro benzoyl, methoxycarbonyl, ethoxycarbonyl, butoxy carbonyl, tertbutyloxycarbonyl, phenyl-diformyl base, benzyl, carbobenzoxy-(Cbz) or to the nitro carbobenzoxy-(Cbz) particularly preferably are tertbutyloxycarbonyl.
Above-mentioned R 9" C in the definition 1-C 5Alkyl " can be the straight or branched alkyl that such as methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl, amyl group, isopentyl, 2-methyl butyl, neo-pentyl or 1-ethyl propyl etc. contains 1-5 carbon atom, preferably C 1-C 3Alkyl is more preferably methyl, ethyl or sec.-propyl.
Above-mentioned R 9" C in the definition 6-C 14Aryl " can be the aromatic hydrocarbyl that such as phenyl, indenyl, naphthyl, phenanthryl or anthryl etc. contains 6-14 carbon atom, preferably phenyl or naphthyl is more preferably phenyl.
Above-mentioned R 9" C in the definition 7-C 14Aralkyl " can be to be attached to " C such as benzyl, α-menaphthyl, indenes methyl, diphenyl-methyl, 2-phenylethyl, 2-α-menaphthyl ethyl, 3-phenyl propyl, 3-Alpha-Naphthyl propyl group, benzene butyl, 4-Alpha-Naphthyl butyl or 5-phenylpentyl etc. by 1 or 2 aromatic hydrocarbyls that contain 6-14 carbon atom 1-C 5Alkyl " go up and the group of formation, preferably benzyl, α-menaphthyl, diphenyl-methyl or 2-phenylethyl are more preferably benzyl or 2-phenylethyl, particularly preferably are benzyls.
Above-mentioned R 10" C in the definition 1-C 6Alkanoyl " can be the alkanoyl that such as formyl radical, ethanoyl, propionyl, butyryl radicals, isobutyryl, valeryl, pentanoyl, isovaleryl or caproyl etc. contains the straight or branched of 1-6 carbon atom, preferably C 1-C 4Alkanoyl particularly preferably is ethanoyl.
Above-mentioned R 10" the C that is replaced by shielded hydroxyl in the definition 2-C 6Alkanoyl " in " C 2-C 6Alkanoyl " can be above-mentioned " C partly 1-C 6Alkanoyl " in contain the alkanoyl of the straight or branched of 2-6 carbon atom, C preferably 2-C 4Alkanoyl is more preferably ethanoyl.
Above-mentioned R 11" C in the definition 1-C 6Alkyl " can be for example methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl, amyl group, isopentyl, 2-methyl butyl, neo-pentyl, 1-ethyl propyl, hexyl, 4-methyl amyl, 3-methyl amyl, 2-methyl amyl, 1-methyl amyl, 3; 3-dimethylbutyl, 2; 2-dimethylbutyl, 1; 1-dimethylbutyl, 1; 2-dimethylbutyl, 1; 3-dimethylbutyl, 2,3-dimethylbutyl or 2-ethyl-butyl etc. contain the straight or branched alkyl of 1-6 carbon atom, preferably C 1-C 4Alkyl, more preferably methyl or ethyl, particularly preferably ethyl.
" halogen atom " in the above-mentioned X definition is for example fluorine atom, chlorine atom, bromine atoms or iodine atom.
Method A is the manufacture method of general formula (I) compound.
Steps A 1 is to make the step of logical formula V compound, and the compound that this can be by making general formula (III) and the compound of general formula (IV) carry out condensation in the presence of phosphine-derivatives or azo-compound in inert solvent finishes.
Employed solvent is not particularly limited, so long as do not hinder reaction and can initial substance dissolving person all can be used.The example of such solvent is the aliphatic hydrocarbon such as hexane, heptane, solvent naphtha or sherwood oil; The aromatic hydrocarbons such as benzene, toluene or dimethylbenzene; The halohydrocarbon such as methylene dichloride, chloroform, tetracol phenixin, ethylene dichloride, chlorobenzene or dichlorobenzene; Or the ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF), diox, glycol dimethyl ether or diglyme, preferably aliphatic hydrocarbon, aromatic hydrocarbons, halogenated hydrocarbon or ethers are more preferably halogenated hydrocarbon (methylene dichloride) or ethers (particularly diethyl ether or tetrahydrofuran (THF)).
Employed phosphine-derivatives can be three (C such as trimethyl-phosphine, triethyl phosphine, tripropyl phosphine, tributylphosphine, three amyl group phosphines or three hexyl phosphines 1-C 6Alkyl) phosphine; Three (the C such as triphenylphosphine, three indenyl phosphines or three naphthyl phosphines 6-C 10Aryl) phosphine; Or tolyl diphenylphosphine, trimethylphenyl phosphine, three _ basic phosphine, tributyl Phenylphosphine or three (6-ethyl-2-naphthyl) phosphine etc. are with C 1-C 4Three (C of alkyl substituent 6-C 10Aryl) phosphine, preferably three (C 1-C 6Alkyl) phosphine (especially trimethyl-phosphine, triethyl phosphine, tripropyl phosphine or tributylphosphine) or three (C 6-C 10Aryl) phosphine (especially triphenylphosphine, three indenyl phosphines or three naphthyl phosphines) is more preferably tributylphosphine or triphenylphosphine.
Employed azo-compound can be azo dicarbapentaborane two piperidines for example, or the azoformic acid two (C such as azo acid dimethyl ester, diethyl azodiformate, azoformic acid dipropyl or azoformic acid dibutylester 1-C 4Alkyl) ester, preferably azo dicarbapentaborane two piperidines, azo acid dimethyl ester or diethyl azodiformate.
Temperature of reaction changes with starting compound and reagent etc., but normally-50 ℃-100 ℃, preferably 0 ℃-60 ℃.
Reaction times changes with starting compound, reagent and temperature of reaction, but normally 5 minutes-24 hours, preferably 10 minutes-6 hours.
React complete after, from reaction mixture, isolate according to a conventional method the purpose compound of this step.For example, react complete after, in the situation that there is insolubles, reaction mixture is filtered, then steam solvent, perhaps, react complete after, steam first solvent, the gained residue is poured into water, adding extracts with the immiscible solvent of water (such as benzene, ether, ethyl acetate etc.), extraction liquid washes with water, then the organic layer anhydrous magnesium sulfate drying steams solvent, obtains the purpose compound.If necessary, can according to a conventional method, such as passing through the methods such as recrystallization, redeposition or chromatogram resulting compound further be made with extra care.
Steps A 2 is to make the step of general formula (I) compound, and this finishes by the following reaction of appropriate combination:
(a) cyano group changes the reaction of amidino groups into,
(b) remove the reaction of the protecting group of shielded amino,
(c) amino acetimidoyl reaction, and, if desired,
(d) hydrolysis reaction of ester, and
(e) remove the reaction of the protecting group of shielded hydroxyl.
" cyano group is transformed into the reaction of amidino groups " as the reaction (a) of necessity can finish by following reaction according to method well known in the art usually:
(1) make starting compound in inert solvent or do not have under the condition of solvent (preferably in inert solvent) in the presence of acid with the alcohols reaction, then make the intermediate imido ether compound of ammonolysis that generates, perhaps
(2) make starting compound in inert solvent, react with hydroxylamine compounds in the existence of alkali or not, then make the intermediate amidoxim compound hydrogenolysis that generates.
Reaction (a) (1) is 2 step reaction.First step is to make nitrile and alcohol reaction obtain the reaction of imido ether compound in the presence of acid.
Employed solvent is not particularly limited, so long as do not hinder reaction and can initial substance dissolving person all can be used.The example of such solvent is the aliphatic hydrocarbon such as hexane, hexanaphthene, heptane, solvent naphtha or sherwood oil; The aromatic hydrocarbons such as benzene, toluene or dimethylbenzene; Methylene dichloride, chloroform, tetracol phenixin, 1, the halohydrocarbon such as 2-ethylene dichloride, chlorobenzene or dichlorobenzene; The ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF), diox, glycol dimethyl ether or diglyme; The ketone such as acetone or methylethylketone; The ester such as methyl acetate or ethyl acetate class; The nitro-compound classes such as Nitromethane 99Min.; The amidess such as methane amide, DMF, N,N-dimethylacetamide or METHYLPYRROLIDONE; The sulfoxide type such as dimethyl sulfoxide (DMSO) or tetramethylene sulfone; Or the mixed solvent of above-mentioned organic solvent, preferably aromatic hydrocarbons (especially benzene) or halogenated hydrocarbon (particularly methylene dichloride), particularly preferably halogenated hydrocarbon (especially methylene dichloride).
In addition, this reaction can be carried out in as the excessive alcohols of reagent and solvent (for example methyl alcohol, ethanol, propyl alcohol, 2-propyl alcohol, butanols or isopropylcarbinol, particular methanol or ethanol), usually carries out in the alcohol that does not hinder reaction.
Employed acid can be mineral acids such as hydrogenchloride, hydrochloric acid, Hydrogen bromide, hydroiodic acid HI, nitric acid, perchloric acid, sulfuric acid or phosphoric acid; The sulfonic acid such as methylsulfonic acid, trifluoromethanesulfonic acid, ethyl sulfonic acid, Phenylsulfonic acid or tosic acid; Perhaps Lewis acids such as boron trifluoride, aluminum chloride, iron(ic) chloride (III), zinc chloride, mercury chloride (II), preferred mineral acid or Lewis acid, particularly preferably hydrogenchloride.
Temperature of reaction changes with starting compound and reagent etc., but normally-10 ℃-100 ℃, preferred 0 ℃-50 ℃.
Reaction times changes with starting compound, reagent and temperature of reaction, but normally 10 minutes-48 hours, preferred 1 hour-15 hours.
React complete after, can (for example steam the method for solvent) according to a conventional method and from reaction mixture, isolate the purpose compound of this reaction, reaction product needn't just can be used for next step reaction by separation and purification in some cases.
The second step of reaction (a) (1) is the reaction that makes the imido ether compound of ammonolysis that generates in the first step.This reaction is carried out in the presence of ammonium ion in inert solvent usually.
Employed solvent is not particularly limited, so long as do not hinder reaction and can initial substance dissolving person all can be used.The example of such solvent can be the alcohols such as methyl alcohol, ethanol, propyl alcohol, 2-propyl alcohol, butanols or isopropylcarbinol; Water; Or the mixed solvent of alcohols and water, particular methanol, ethanol, water, aqueous methanol or aqueous ethanol, particularly preferably aqueous methanol or aqueous ethanol.
The ammonium source of employed ammonium ion can be for example ammoniacal liquor, ammonium chloride, volatile salt or their mixture, preferred ammonium chloride.
PH is neutral to weakly alkaline in the reaction, preferably uses ammoniacal liquor and hydrochloric acid that pH regulator is arrived 7-9.
Temperature of reaction changes with starting compound and reagent etc., but normally-10 ℃-100 ℃, preferred 0 ℃-50 ℃.
Reaction times changes with starting compound, reagent and temperature of reaction, but normally 10 minutes-48 hours, preferred 1 hour-15 hours.
React complete after, from reaction mixture, isolate according to a conventional method the purpose compound of this reaction.For example, react complete after, steam solvent, or react complete after, in reaction mixture, add entry, add and the immiscible solvent of water (such as benzene, ether, ethyl acetate etc.) again, extract the purpose compound, the organic layer that extracts washes with water, with dryings such as anhydrous magnesium sulfates, then steam solvent, obtain the purpose compound.If necessary, can according to a conventional method, such as passing through the methods such as recrystallization, redeposition or chromatogram resulting purpose compound further be made with extra care.
Reaction (a) (2) are 2 step reaction.At first, first step is in inert solvent, talks about as desired in the presence of alkali, makes the reaction of nitrile and oxyamine obtain the reaction of amidoxim compound.
Employed solvent is not particularly limited, so long as do not hinder reaction and can initial substance dissolving person all can be used.The example of such solvent is the aliphatic hydrocarbon such as hexane, hexanaphthene, heptane, solvent naphtha or sherwood oil; The aromatic hydrocarbons such as benzene, toluene or dimethylbenzene; Methylene dichloride, chloroform, tetracol phenixin, 1, the halohydrocarbon such as 2-ethylene dichloride, chlorobenzene or dichlorobenzene; The ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF), diox, glycol dimethyl ether or diglyme; The ketone such as acetone or methylethylketone; The nitro-compound classes such as Nitromethane 99Min.; The nitrile such as acetonitrile or isopropyl cyanide; The alcohols such as methyl alcohol, ethanol, propyl alcohol, 2-propyl alcohol, butanols or isopropylcarbinol; The amidess such as methane amide, DMF, N,N-dimethylacetamide or METHYLPYRROLIDONE; The sulfoxide type such as dimethyl sulfoxide (DMSO) or tetramethylene sulfone; Or water, preferred alcohols (particularly methyl alcohol or ethanol).
As the supply source of employed oxyamine, can enumerate the aqueous solution, the solution of oxyamine in organic solvent or the additive salt of oxyamine and acid of oxyamine.
Employed alkali is not particularly limited, as long as the alkali of its neutralization just can be able to be used (when directly using the solution of oxyamine, always do not need to use alkali) when using the additive salt of oxyamine and acid.The example of such alkali can be alkaline carbonate classes such as yellow soda ash, salt of wormwood or Quilonum Retard; The alkali metal hydrocarbonate classes such as sodium bicarbonate, saleratus or lithium bicarbonate; The alkali metal acetate classes such as sodium acetate; The alkali metal hydroxides such as sodium hydroxide, potassium hydroxide or lithium hydroxide; The alkali metal alcohol salts such as sodium methylate, sodium ethylate, potassium tert.-butoxide or lithium methoxide; Or triethylamine, Tributylamine, diisopropyl ethyl amine, N-methylmorpholine, pyridine, 4-(N, the N-dimethylamino) pyridine, N, accelerine, N, N-Diethyl Aniline, 1,5-diazabicyclo [4.3.0] ninth of the ten Heavenly Stems-5-alkene, 1, the 4-diazabicyclo (2.2.2] octane (DABCO) or 1,8-diazabicyclo [5.4.0] 11 carbon-organic bases, preferred alkali metal carbonate class (especially yellow soda ash) or alkali metal alcohol salts (especially potassium tert.-butoxide) such as 7-alkene (DBU).
Temperature of reaction changes with starting compound and reagent etc., but normally 0 ℃-150 ℃, preferred 50 ℃-100 ℃.
Reaction times changes with starting compound, reagent and temperature of reaction, but normally 1-4 hour, preferred 5-12 hour.
React complete after, can (for example steam the method for solvent) according to a conventional method and from reaction mixture, isolate the purpose compound of this reaction, reaction product needn't just can be used for next step reaction by separation and purification in some cases.
The second step of reaction (a) (2) is the reaction that makes the amidoxim compound hydrogenolysis that generates in the first step.
Usually, before hydrogenolysis, make first hydroxyl change into leavings group, usually use simply ethanoyl, acetylization reaction usually in acetic acid, to carry out with diacetyl oxide, can in solvent, carry out in case of necessity.
In the acetylization reaction, employed solvent is not particularly limited, so long as do not hinder reaction and can initial substance dissolving person all can be used.The example of such solvent is the aliphatic hydrocarbon such as hexane, hexanaphthene, heptane, solvent naphtha or sherwood oil; The aromatic hydrocarbons such as benzene, toluene or dimethylbenzene; Methylene dichloride, chloroform, tetracol phenixin, 1, the halohydrocarbon such as 2-ethylene dichloride, chlorobenzene or dichlorobenzene; The ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF), diox, glycol dimethyl ether or diglyme; The ketone such as acetone or methylethylketone; The nitro-compound classes such as Nitromethane 99Min.; The perhaps nitrile such as acetonitrile or isopropyl cyanide, preferred halogenated hydrocarbon (especially methylene dichloride) or ethers (especially tetrahydrofuran (THF)).
Acetylizad temperature of reaction changes with starting compound and reagent etc., but normally 0 ℃-150 ℃, preferred 10 ℃-50 ℃.
The acetylizad reaction times changes with starting compound, reagent and temperature of reaction, but normally 1-24 hour, preferred 5-12 hour.
React complete after, can (for example steam the method for solvent) according to a conventional method and from reaction mixture, isolate the purpose compound of this reaction, reaction product needn't just can be used for next step reaction by separation and purification in some cases.
The hydrogenolysis of amidoxim compound when glycoloyl or desacetoxy (in the situation that) carries out not changing solvent usually.In addition, if desired, can first solvent be steamed, the gained residue is dissolved in the inert solvent again, and then carries out hydrogenolysis.
Employed solvent is not particularly limited, so long as do not hinder reaction and can initial substance dissolving person all can be used.The example of such solvent is the aliphatic hydrocarbon such as hexane, hexanaphthene, heptane, solvent naphtha or sherwood oil; The aromatic hydrocarbons such as benzene, toluene or dimethylbenzene; Methylene dichloride, chloroform, tetracol phenixin, 1, the halohydrocarbon such as 2-ethylene dichloride, chlorobenzene or dichlorobenzene; The ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF), diox, glycol dimethyl ether or diglyme; The ketone such as acetone or methylethylketone; The nitro-compound classes such as Nitromethane 99Min.; The nitrile such as acetonitrile or isopropyl cyanide; The alcohols such as methyl alcohol, ethanol, propyl alcohol, 2-propyl alcohol, butanols or isopropylcarbinol; The amidess such as methane amide, DMF, N,N-dimethylacetamide or METHYLPYRROLIDONE; The sulfoxide type such as dimethyl sulfoxide (DMSO) or tetramethylene sulfone; The carboxylic-acid such as formic acid or acetic acid; Water; Or the mixed solvent of above-mentioned solvent, preferred alcohols (especially methyl alcohol or ethanol), acetic acid or its mixed solvent.
Employed catalyzer is not particularly limited in the hydrogenolysis, all can use as long as can be used for common catalytic reduction reaction person.The example of this catalyzer can be that for example palladium black, palladium charcoal, palladium hydroxide, charcoal carry palladium hydroxide, Raney nickel, rhodium-aluminum oxide, palladium-barium sulfate, platinum oxide or platinum black, preferred palladium charcoal.
Temperature of reaction changes with starting compound and reagent etc., but normally-10 ℃-100 ℃, preferred 0 ℃-80 ℃.
Reaction times changes with starting compound, reagent and temperature of reaction, but normally 1-24 hour, preferred 5-12 hour.
React complete after, from reaction mixture, isolate according to a conventional method the purpose compound of this reaction.For example react complete after, by removing by filter catalyzer, then steam solvent, perhaps, react complete rear filtration catalizer, then in reaction mixture, add entry, add and the immiscible solvent of water (such as benzene, ether, ethyl acetate etc.) again, extract the purpose compound, the organic layer that extracts washes with water, with dryings such as anhydrous magnesium sulfates, then steam solvent, obtain the purpose compound.If necessary, can according to a conventional method, such as passing through the methods such as recrystallization, redeposition or chromatogram resulting purpose compound further be made with extra care.
" removing the reaction of the protecting group of shielded amino " as the reaction (b) of necessity carries out according to known method in the general Synthetic Organic Chemistry technology, and be specific as follows:
When amino protecting group is formyl radical, ethanoyl, benzoyl, methoxycarbonyl, ethoxycarbonyl, tertbutyloxycarbonyl, 2-trimethyl silyl ethoxycarbonyl, 2-bromine tertbutyloxycarbonyl, 2; 2-dibromo tertbutyloxycarbonyl, ethylene oxy carbonyl, carbobenzoxy-(Cbz), (1-phenyl) carbobenzoxy-(Cbz), 9-anthracene methoxycarbonyl, during to methoxyl group benzyloxy carbonyl or to the nitro carbobenzoxy-(Cbz), can be by in inert solvent or aqueous solvent, removing this amino protecting group with acid treatment.
Employed acid can be for example hydrochloric acid, sulfuric acid, phosphoric acid, Hydrogen bromide or trifluoroacetic acid, preferred hydrochloric acid, sulfuric acid, Hydrogen bromide or trifluoroacetic acid.
Employed solvent is not particularly limited, so long as do not hinder reaction and can initial substance dissolving person all can be used.The example of such solvent is the aliphatic hydrocarbon such as hexane, heptane, solvent naphtha or sherwood oil; The aromatic hydrocarbons such as benzene, toluene or dimethylbenzene; The halohydrocarbon such as methylene dichloride, chloroform, tetracol phenixin, ethylene dichloride, chlorobenzene or dichlorobenzene; The ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF), diox, glycol dimethyl ether or diglyme; The ester such as methyl acetate or ethyl acetate class; The alcohols such as methyl alcohol, ethanol, propyl alcohol, 2-propyl alcohol or butanols; The amidess such as methane amide, DMF, N,N-dimethylacetamide or hexamethyl phosphoric triamide; The sulfoxide type such as dimethyl sulfoxide (DMSO) or tetramethylene sulfone; The fatty acid such as formic acid or acetic acid; The perhaps mixed solvent of water or water and above-mentioned solvent.Preferred solvent is the mixed solvent of halogenated hydrocarbon, ethers, alcohols, fatty acid or water and above-mentioned solvent, be more preferably halogenated hydrocarbon (especially methylene dichloride), ethers (tetrahydrofuran (THF) Huo diox), fatty acid (especially acetic acid), alcohols (especially methyl alcohol or ethanol), the perhaps mixed solvent of water or water and above-mentioned solvent.
Temperature of reaction changes with starting compound, solvent or employed acid, but normally-10 ℃-150 ℃, preferred 0 ℃-100 ℃.
Reaction times changes with starting compound, solvent or employed acid, but normally 5 minutes-48 hours, preferred 10 minutes-15 hours.
React complete after, from reaction mixture, isolate according to a conventional method the purpose compound of this reaction.For example, can collect the purpose compound of separating out in the reaction mixture by filtering, in case of necessity, suitably neutralize, steam solvent, carry out again drying, perhaps, reaction mixture is poured into water, suitably neutralizes in case of necessity, add and the immiscible solvent of water (such as benzene, ether, ethyl acetate etc.), extract, the organic layer that contains the purpose compound washes with water, with dryings such as anhydrous magnesium sulfates, then steam solvent, obtain the purpose compound.If necessary, can according to a conventional method, such as passing through the methods such as recrystallization, redeposition or chromatogram resulting purpose compound further be made with extra care.
Alkanoyl at amino protecting group, in the situation of aryl carbonyl, carbalkoxy, chain ene keto carbonyl, aryl dicarbapentaborane, aralkyl or aralkoxycarbonyl, can be by in inert solvent or aqueous solvent, removing amino protecting group with alkaline purification.
Employed alkali can be alkaline carbonate classes such as yellow soda ash, salt of wormwood or Quilonum Retard; The alkali metal hydrocarbonate classes such as sodium bicarbonate, saleratus or lithium bicarbonate; The alkalimetal hydride classes such as lithium hydride, sodium hydride or potassium hydride KH; The alkali metal hydroxides such as sodium hydroxide, potassium hydroxide or lithium hydroxide; The alkali metal alcohol salts such as sodium methylate, sodium ethylate, potassium tert.-butoxide or lithium methoxide; The alkali metal mercaptides such as sodium methyl mercaptide or sulfur alcohol sodium; Hydrazine, methylamine, dimethylamine, ethamine, triethylamine, Tributylamine, diisopropyl ethyl amine, N-methylmorpholine, pyridine, 4-(N, the N-dimethylamino) pyridine, N, accelerine, N, the N-Diethyl Aniline, 1,5-diazabicyclo [4.3.0] ninth of the ten Heavenly Stems-5-alkene, 1,4-diazabicyclo [2.2.2] octane (DABCO) or 1,8-diazabicyclo [5.4.0] 11 carbon-organic bases such as 7-alkene (DBU), preferred alkali metal carbonate class (especially yellow soda ash or salt of wormwood), alkali metal hydroxide (especially sodium hydroxide or potassium hydroxide), alkali metal alcohol salt (sodium methylate especially, sodium ethylate or potassium tert.-butoxide) or organic bases (especially hydrazine or methylamine).
Employed solvent is not particularly limited, so long as do not hinder reaction and can initial substance dissolving person all can be used.The example of such solvent is the aliphatic hydrocarbon such as hexane, heptane, solvent naphtha or sherwood oil; The aromatic hydrocarbons such as benzene, toluene or dimethylbenzene; The halohydrocarbon such as methylene dichloride, chloroform, tetracol phenixin, ethylene dichloride, chlorobenzene or dichlorobenzene; The ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF), diox, glycol dimethyl ether or diglyme; The alcohols such as methyl alcohol, ethanol, propyl alcohol, 2-propyl alcohol or butanols; The amidess such as methane amide, DMF, N,N-dimethylacetamide or hexamethyl phosphoric triamide; The sulfoxide type such as dimethyl sulfoxide (DMSO) or tetramethylene sulfone; Or the mixed solvent of water and above-mentioned solvent.Preferred solvent is the mixed solvent of halogenated hydrocarbon, ethers, alcohols or water and above-mentioned solvent, is more preferably ethers (tetrahydrofuran (THF) Huo diox), alcohols (especially methyl alcohol or ethanol), or the mixed solvent of water and above-mentioned solvent.
Temperature of reaction changes with starting compound, solvent or employed acid, but normally-10 ℃-50 ℃, preferred-5 ℃-10 ℃.
Reaction times changes with starting compound, solvent or employed acid, but normally 5 minutes-20 hours, preferred 10 minutes-3 hours.
React complete after, from reaction mixture, isolate according to a conventional method the purpose compound of this reaction.For example, can collect the purpose compound of separating out in the reaction mixture by filtering, or, with the acid neutralization, then steam solvent, perhaps in case of necessity, in reaction mixture, add entry, regulate the pH of water layer, filter and collect the throw out that forms, perhaps add and the immiscible solvent of water (such as benzene, ether, ethyl acetate etc.), extract, the organic layer that contains the purpose compound washes with water, with dryings such as anhydrous magnesium sulfates, then steam solvent, obtain the purpose compound.If necessary, can according to a conventional method, such as passing through the methods such as recrystallization, redeposition or chromatogram resulting purpose compound further be made with extra care.
In addition, when amino protecting group is tertbutyloxycarbonyl, can be by in inert solvent, processing to remove this amino protecting group with silyl compound or Lewis acid.
As employed silyl compound, can enumerate for example trimethylsilyl chloride, trimethyl silyl iodine or trifluoromethanesulfonic acid trimethyl silyl ester.As employed Lewis acid, can enumerate for example aluminum chloride.
Employed solvent is not particularly limited, so long as do not hinder reaction and can initial substance dissolving person all can be used.The example of such solvent can be the halogenated hydrocarbons such as methylene dichloride, chloroform or tetracol phenixin; The ethers such as ether, tetrahydrofuran (THF) Huo diox; Or the nitrile such as acetonitrile, preferred halogenated hydrocarbon (especially methylene dichloride or chloroform) or nitrile (especially acetonitrile).
Temperature of reaction changes with starting compound, reagent or solvent etc., but normally-20 ℃-100 ℃, preferred 0 ℃-50 ℃.
Reaction times changes with starting compound, reagent, solvent or temperature of reaction etc., but normally 10 minutes-10 hours, preferred 30 minutes-3 hours.
React complete after, from reaction mixture, isolate according to a conventional method the purpose compound of this reaction.For example by steaming solvent, in reaction mixture, add entry, with the water layer alkalization, filter and collect precipitate, perhaps, add and the immiscible solvent of water (such as benzene, ether, ethyl acetate etc.), extract, the organic layer that contains the purpose compound washes with water, with dryings such as anhydrous magnesium sulfates, then steam solvent, obtain the purpose compound.If necessary, can according to a conventional method, such as passing through the methods such as recrystallization, redeposition or chromatogram resulting purpose compound further be made with extra care.
In addition, when amino protecting group is allyloxycarbonyl, can be by removing this amino protecting group with the same method of removing of the catalytic reduction reaction of aralkyl.That is, can remove this amino protecting group with palladium and triphenylphosphine or nickel tetracarbonyl.
When amino protecting group is aralkyl or C 7-C 11During aralkoxycarbonyl, usually can be by in inert solvent, contacting (preferably in the presence of catalyzer, carrying out catalytic reduction) with reductive agent or removing this amino protecting group with the method for oxygenant.
In the situation that remove protecting group by catalytic reduction, employed solvent is not particularly limited, so long as do not hinder this reactor all can use.Such solvent can be aliphatic hydrocarbon such as hexane or hexanaphthene; The aromatic hydrocarbons such as toluene, benzene or dimethylbenzene; The ethers such as ether, tetrahydrofuran (THF) Huo diox; The ester such as ethyl acetate or propyl acetate class; The alcohols such as methyl alcohol, ethanol or 2-propyl alcohol; The fatty acid such as formic acid or acetic acid; Or the mixed solvent of above-mentioned organic solvent and water, the mixed solvent of preferred aliphatic series hydro carbons, aromatic hydrocarbons, ethers, ester class, alcohols, fatty acid or these organic solvents and water, more preferably alcohols (especially methyl alcohol or ethanol), fatty acid (especially formic acid or acetic acid), or the mixed solvent of these organic solvents and water.
Employed catalyzer so long as can be used for common catalytic reduction reaction person, just has no particular limits, and its example can be enumerated for example palladium charcoal, Raney nickel, rhodium-aluminum oxide or palladium-barium sulfate, preferred palladium charcoal or Raney nickel.
Reaction pressure is not particularly limited, but normally 1-10 normal atmosphere, preferably 1 air pressure.
Temperature of reaction changes with starting compound, solvent or employed reductive agent etc., but normally 0 ℃-100 ℃, preferred 10 ℃-50 ℃.
Reaction times changes with starting compound, solvent, employed reductive agent or temperature of reaction etc., but normally 15 minutes-24 hours, preferred 30 minutes-12 hours.
React complete after, from reaction mixture, isolate according to a conventional method the purpose compound of this reaction.For example by removing by filter catalyzer, then steam solvent, in reaction mixture, add entry, water layer is alkalized, filter and collect precipitate, perhaps, add and the immiscible solvent of water (such as benzene, ether, ethyl acetate etc.), extract, the organic layer that contains the purpose compound washes with water, with dryings such as anhydrous magnesium sulfates, then steam solvent, obtain the purpose compound.If necessary, can according to a conventional method, such as passing through the methods such as recrystallization, redeposition or chromatogram resulting purpose compound further be made with extra care.
Employed solvent is not particularly limited in the method for removing protecting group by oxidation, so long as do not hinder this reactor all can use.Such solvent can be such as ketones such as acetone; The halogenated hydrocarbons such as methylene dichloride, chloroform or tetracol phenixin; The nitriles such as acetonitrile; The ethers such as ether, tetrahydrofuran (THF) Huo diox; The amidess such as DMF, N,N-dimethylacetamide or hexamethyl phosphoric triamide; The sulfoxide types such as dimethyl sulfoxide (DMSO); Or the mixed solvent of these organic solvents and water, the mixed solvent of preferred ketone, halogenated hydrocarbon, nitrile, ethers, amides, sulfoxide type or these organic solvents and water, the more preferably mixed solvent of ketone (especially acetone), halogenated hydrocarbon (especially methylene dichloride), nitrile (especially acetonitrile), amides (especially hexamethyl phosphoric triamide), sulfoxide type (especially dimethyl sulfoxide (DMSO)) or these organic solvents and water.
Employed oxygenant can be for example Potassium Persulphate, Sodium Persulfate, ceric ammonium nitrate (CAN) or 2,3-, two chloro-5,6-dicyano-para benzoquinone (DDQ), preferred CAN or DDQ.
Temperature of reaction changes with starting compound, solvent or employed oxygenant etc., but normally 0 ℃-150 ℃, preferred 10 ℃-50 ℃.
Reaction times changes with starting compound, solvent or employed oxygenant etc., but normally 15 minutes-24 hours, preferred 30 minutes-12 hours.
React complete after, from reaction mixture, isolate according to a conventional method the purpose compound of this reaction.For example by removing by filter oxygenant, then steam solvent, in reaction mixture, add entry, water layer is alkalized, filter and collect precipitate, perhaps, add and the immiscible solvent of water (such as benzene, ether, ethyl acetate etc.), extract, the organic layer that contains the purpose compound washes with water, with dryings such as anhydrous magnesium sulfates, then steam solvent, obtain the purpose compound.If necessary, can according to a conventional method, such as passing through the methods such as recrystallization, redeposition or chromatogram resulting purpose compound further be made with extra care.
As " the amino acetimidoyl " of the reaction (c) of necessity be by make starting compound in inert solvent in the existence of alkali or not (preferably in the presence of alkali) realize with second imido acid ethyl ester or iminoester hydrochloride (preferred iminoester hydrochloride) reaction.
Employed solvent is not particularly limited in the reaction (c), so long as do not hinder reaction and can initial substance dissolving person all can be used.The example of such solvent is the aliphatic hydrocarbon such as hexane, hexanaphthene, heptane, solvent naphtha or sherwood oil; The aromatic hydrocarbons such as benzene, toluene or dimethylbenzene; Methylene dichloride, chloroform, tetracol phenixin, 1, the halohydrocarbon such as 2-ethylene dichloride, chlorobenzene or dichlorobenzene; The ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF), diox, glycol dimethyl ether or diglyme; The ketone such as acetone or methylethylketone; The nitro-compound classes such as Nitromethane 99Min.; The nitrile such as acetonitrile or isopropyl cyanide; The alcohols such as methyl alcohol, ethanol, propyl alcohol, 2-propyl alcohol, butanols or isopropylcarbinol; The amidess such as methane amide, DMF, N,N-dimethylacetamide or METHYLPYRROLIDONE; The sulfoxide type such as dimethyl sulfoxide (DMSO) or tetramethylene sulfone, preferred alcohols (especially ethanol).
Employed alkali can be alkaline carbonate classes such as yellow soda ash, salt of wormwood or Quilonum Retard in the reaction (c); The alkali metal hydrocarbonate classes such as sodium bicarbonate, saleratus or lithium bicarbonate; The alkali metal hydroxides such as sodium hydroxide, potassium hydroxide or lithium hydroxide; Perhaps triethylamine, Tributylamine, diisopropyl ethyl amine, N-methylmorpholine, pyridine, 4-(N, the N-dimethylamino) pyridine, N, accelerine, N, N-Diethyl Aniline, 1,5-diazabicyclo [4.3.0] ninth of the ten Heavenly Stems-5-alkene, 1,4-diazabicyclo [2.2.2] octane (DABCO) or 1,8-diazabicyclo [5.4.0] 11 carbon-organic bases, preferred alkali metal carbonate class (yellow soda ash or salt of wormwood) or organic bases (especially triethylamine) such as 7-alkene (DBU).
Temperature of reaction changes with starting compound and reagent etc., but normally-10 ℃-100 ℃, preferred 0 ℃-50 ℃.
Reaction times changes with starting compound, reagent and temperature of reaction, but normally 1-48 hour, preferably 5-15 hour.
React complete after, from reaction mixture, isolate according to a conventional method the purpose compound of this reaction.For example, react complete after, steam solvent, or react complete after, in reaction mixture, add entry, add and the immiscible solvent of water (such as benzene, ether, ethyl acetate etc.) again, extract the purpose compound, the organic layer that extracts washes with water, with dryings such as anhydrous magnesium sulfates, then steam solvent, obtain the purpose compound.If necessary, can according to a conventional method, such as passing through the methods such as recrystallization, redeposition or chromatogram resulting purpose compound further be made with extra care.
" hydrolysis reaction of ester " as optional reaction (d) can be according to known method in the general Synthetic Organic Chemistry technology, by making starting compound in inert solvent or not existing under the condition of solvent, in the presence of acid or alkali, be hydrolyzed to realize, preferably in the presence of acid, be hydrolyzed.
Employed solvent is not particularly limited, so long as do not hinder reaction and can initial substance dissolving person all can be used.The example of such solvent can be the mixed solvent of the alcohols such as methyl alcohol, ethanol, propyl alcohol, 2-propyl alcohol, butanols or isopropylcarbinol and water, preferred aqueous methanol or aqueous ethanol.
Employed acid can be mineral acids such as hydrochloric acid, Hydrogen bromide, hydroiodic acid HI, nitric acid, perchloric acid, sulfuric acid or phosphoric acid; The sulfonic acid such as methylsulfonic acid, trifluoromethanesulfonic acid, ethyl sulfonic acid, Phenylsulfonic acid or tosic acid; Or the carboxylic acids such as fumaric acid, succsinic acid, citric acid, tartrate, oxalic acid or toxilic acid, preferred mineral acid (especially hydrochloric acid).
Employed alkali can be alkaline carbonate classes such as yellow soda ash, salt of wormwood or Quilonum Retard; The alkali metal hydrocarbonate classes such as sodium bicarbonate, saleratus or lithium bicarbonate; Or the alkali metal hydroxides such as sodium hydroxide, potassium hydroxide or lithium hydroxide, preferred sodium hydroxide.
Temperature of reaction changes with starting compound and reagent etc., in the reaction of using acid, normally 0 ℃-150 ℃ (preferred 50 ℃-100 ℃), in the reaction of using alkali, normally-10 ℃-50 ℃ (preferred-5 ℃-10 ℃).
Reaction times changes with starting compound, reagent and temperature of reaction, in the reaction of using acid, normally 30 minutes-48 hours (preferred 3-10 hour), in the reaction of using alkali, normally 5 minutes-10 hours (preferred 10 minutes-3 hours).
React complete after, from reaction mixture, isolate according to a conventional method the purpose compound of this step.For example, react complete after, steam solvent, or react complete after, with acid (for example hydrochloric acid) with the reaction mixture acidifying.Filter and collect the purpose compound of separating out, or adding and the immiscible solvent of water (such as benzene, ether, ethyl acetate etc.), extract the purpose compound, the organic layer that extracts washes with water, with dryings such as anhydrous magnesium sulfates, then steam solvent, obtain the purpose compound.In addition, react complete after, also can be by in the aqueous solution of reaction mixture, passing into carbon dioxide gas or adding yellow soda ash or salt of wormwood, to obtain the carbonate of purpose compound.If necessary, can according to a conventional method, such as passing through the methods such as recrystallization, redeposition or chromatogram resulting purpose compound further be made with extra care.
" removing the reaction of the protecting group of shielded hydroxyl " as optional reaction (e) can be according to for example " protecting group in the organic synthesis " (Protective Groups in OrganicSynthesis), the third edition, T.W.Green and P.G.M.Wuts, John Wiley ﹠amp; Sons, method described in the Inc. is carried out.
In the situation that hydroxyl protecting group is following groups, can be by removing this protecting group with acid-treated method in inert solvent or in the aqueous solvent.Described group is: formyl radical; ethanoyl; benzoyl; tetrahydropyrans-2-base; 3-bromine tetrahydropyrans-2-base; 4-methoxyl group tetrahydropyran-4-base; tetrahydric thiapyran-2-base; 4-methoxyl group tetrahydric thiapyran-4-group; tetrahydrofuran (THF)-2-base or tetramethylene sulfide-2-base; methoxymethyl; 1; 1-dimethyl-1-methoxymethyl; ethoxyl methyl; the propoxy-methyl; the isopropoxy methyl; butoxymethyl; the tert.-butoxy methyl; 2-methoxy ethoxy methyl; 2; 2; 2-trichlorine ethoxyl methyl; two (2-chloroethoxy) methyl; the 1-ethoxyethyl group; 1-(isopropoxy) ethyl; methoxycarbonyl; ethoxycarbonyl; tertbutyloxycarbonyl; 2-trimethyl silyl ethoxycarbonyl; 2-bromo-tertbutyloxycarbonyl; 2,2-, two bromo-tertbutyloxycarbonyls; the ethene carbonyl; carbobenzoxy-(Cbz); (1-phenyl) carbobenzoxy-(Cbz); 9-anthryl methoxycarbonyl; to methoxyl group benzyloxy carbonyl or to the nitro carbobenzoxy-(Cbz).
Employed acid can be for example hydrochloric acid, sulfuric acid, phosphoric acid, Hydrogen bromide or trifluoroacetic acid, preferred hydrochloric acid, sulfuric acid, Hydrogen bromide or trifluoroacetic acid.
Employed solvent is not particularly limited, so long as do not hinder reaction and can initial substance dissolving person all can be used.The example of such solvent is the aliphatic hydrocarbon such as hexane, heptane, solvent naphtha or sherwood oil; The aromatic hydrocarbons such as benzene, toluene or dimethylbenzene; The halohydrocarbon such as methylene dichloride, chloroform, tetracol phenixin, ethylene dichloride, chlorobenzene or dichlorobenzene; The ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF), diox, glycol dimethyl ether or diglyme; The ester such as methyl acetate or ethyl acetate class; The alcohols such as methyl alcohol, ethanol, propyl alcohol, 2-propyl alcohol or butanols; The amidess such as methane amide, DMF, N,N-dimethylacetamide or hexamethyl phosphoric triamide; The sulfoxide type such as dimethyl sulfoxide (DMSO) or tetramethylene sulfone; The fatty acid such as formic acid or acetic acid; The perhaps mixed solvent of water or water and above-mentioned solvent.Preferred solvent is the mixed solvent of halogenated hydrocarbon, ethers, ester class, alcohols, fatty acid or water and above-mentioned solvent, is more preferably the mixed solvent of halogenated hydrocarbon (especially methylene dichloride), ether (especially tetrahydrofuran (THF) Huo diox), ester class (especially ethyl acetate), fatty acid (especially acetic acid) or water or water and above-mentioned solvent.
Temperature of reaction changes with starting compound, solvent or employed acid, but normally-10 ℃-150 ℃, preferred 0 ℃-60 ℃.
Reaction times changes with starting compound, solvent or employed acid, but normally 5 minutes-20 hours, preferred 10 minutes-12 hours.
React complete after, from reaction mixture, isolate according to a conventional method the purpose compound of this step.For example, react complete after, reaction mixture is suitably neutralized, steam solvent, in reaction mixture, add entry, add and the immiscible solvent of water (such as benzene, ether, ethyl acetate etc.) again, extract, the organic layer that contains the purpose compound washes with water, with dryings such as anhydrous magnesium sulfates, then steam solvent, obtain the purpose compound.If necessary, can according to a conventional method, such as passing through the methods such as recrystallization, redeposition or chromatogram resulting purpose compound further be made with extra care.
In the situation that hydroxyl protecting group is following groups, can be by removing this protecting group with the method for alkaline purification in inert solvent or in the aqueous solvent.Described group is: alkanoyl, carboxylated alkanoyl, halogenated alkane acyl group, oxyalkyl chain alkyloyl, unsaturated chain alkyloyl, aryl carbonyl, halogenated aryl carbonyl, alkylated aryl carbonyl, carboxylated aryl carbonyl, nitration aryl carbonyl, alkoxylate aryl carbonyl or arylation aryl carbonyl.
Employed alkali can be alkaline carbonate classes such as yellow soda ash, salt of wormwood or Quilonum Retard; The alkali metal hydrocarbonate classes such as sodium bicarbonate, saleratus or lithium bicarbonate; The alkalimetal hydride classes such as lithium hydride, sodium hydride or potassium hydride KH; The alkali metal hydroxides such as sodium hydroxide, potassium hydroxide or lithium hydroxide; The alkali metal alcohol salts such as sodium methylate, sodium ethylate, potassium tert.-butoxide or lithium methoxide; The alkali metal mercaptides such as sodium methyl mercaptide or sulfur alcohol sodium; Hydrazine, methylamine, dimethylamine, ethamine, triethylamine, Tributylamine, diisopropyl ethyl amine, N-methylmorpholine, pyridine, 4-(N, the N-dimethylamino) pyridine, N, accelerine, N, the N-Diethyl Aniline, 1, the 5-diazabicyclo (4.3.0] ninth of the ten Heavenly Stems-5-alkene, 1,4-diazabicyclo [2.2.2] octane (DABCO) or 1,8-diazabicyclo [5.4.0] 11 carbon-organic bases such as 7-alkene (DBU), preferred alkali metal carbonate class (especially yellow soda ash or salt of wormwood), alkali metal hydroxide (especially sodium hydroxide or potassium hydroxide), alkali metal alcohol salt (sodium methylate especially, sodium ethylate or potassium tert.-butoxide) or organic bases (especially hydrazine or methylamine).
Employed solvent is not particularly limited, so long as do not hinder reaction and can initial substance dissolving person all can be used.The example of such solvent is the aliphatic hydrocarbon such as hexane, heptane, solvent naphtha or sherwood oil; The aromatic hydrocarbons such as benzene, toluene or dimethylbenzene; The halohydrocarbon such as methylene dichloride, chloroform, tetracol phenixin, ethylene dichloride, chlorobenzene or dichlorobenzene; The ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF), diox, glycol dimethyl ether or diglyme; The alcohols such as methyl alcohol, ethanol, propyl alcohol, 2-propyl alcohol or butanols; The amidess such as methane amide, DMF, N,N-dimethylacetamide or hexamethyl phosphoric triamide; The sulfoxide type such as dimethyl sulfoxide (DMSO) or tetramethylene sulfone; Or the mixed solvent of water and above-mentioned solvent.Preferred solvent is the mixed solvent of halogenated hydrocarbon, ethers, alcohols or water and above-mentioned solvent, is more preferably ethers (tetrahydrofuran (THF) Huo diox), alcohols (especially methyl alcohol or ethanol), or the mixed solvent of water and above-mentioned solvent.
Temperature of reaction changes with starting compound, solvent or employed alkali, but normally-10 ℃-150 ℃, preferred 0 ℃-50 ℃.
Reaction times changes with starting compound, solvent or employed alkali, but normally 50 minutes-20 hours, preferred 10 minutes-5 hours.
React complete after, from reaction mixture, isolate according to a conventional method the purpose compound of this step.For example, react complete after, by steaming solvent, in reaction mixture, add entry, then add and the immiscible solvent of water (such as benzene, ether, ethyl acetate etc.), extract, the organic layer that contains the purpose compound washes with water, with dryings such as anhydrous magnesium sulfates, then steam solvent, obtain the purpose compound.If necessary, can according to a conventional method, such as passing through the methods such as recrystallization, redeposition or chromatogram resulting purpose compound further be made with extra care.
When hydroxyl protecting group is aralkyl or aralkoxycarbonyl, usually preferably by the method for removing that in inert solvent, contacts (preferably in the presence of catalyzer, carrying out catalytic reduction) with reductive agent or the method for removing of using oxygenant.
Removing by catalytic reduction in the reaction of protecting group, employed solvent is not particularly limited, so long as do not hinder this reactor all can use.Such solvent can be aliphatic hydrocarbon such as hexane or hexanaphthene; The aromatic hydrocarbons such as toluene, benzene or dimethylbenzene; The ethers such as ether, tetrahydrofuran (THF) Huo diox; The ester such as ethyl acetate or propyl acetate class; The alcohols such as methyl alcohol, ethanol or 2-propyl alcohol; The fatty acid such as formic acid or acetic acid; Or the mixed solvent of above-mentioned organic solvent and water, the mixed solvent of preferred aliphatic series hydro carbons, aromatic hydrocarbons, ethers, ester class, alcohols, fatty acid or these organic solvents and water, more preferably alcohols (especially methyl alcohol or ethanol), fatty acid (especially formic acid or acetic acid), or the mixed solvent of these organic solvents and water.
Employed catalyzer so long as can be used for common catalytic reduction reaction person, just has no particular limits, and its example can be enumerated for example palladium charcoal, Raney nickel, rhodium-aluminum oxide or palladium-barium sulfate, preferred palladium charcoal or Raney nickel.
Reaction pressure is not particularly limited, but normally 1-10 normal atmosphere, preferably 1 air pressure.
Temperature of reaction changes with starting compound, solvent or employed reductive agent etc., but normally 0 ℃-100 ℃, preferred 10 ℃-50 ℃.
Reaction times changes with starting compound, solvent, employed reductive agent or temperature of reaction etc., but normally 15 minutes-10 hours, preferred 30 minutes-3 hours.
React complete after, from reaction mixture, isolate according to a conventional method the purpose compound of this step.For example by removing by filter catalyzer, then steam solvent, add and the immiscible solvent of water (such as benzene, ether, ethyl acetate etc.), extract, the organic layer that contains the purpose compound washes with water, with dryings such as anhydrous magnesium sulfates, then steam solvent, obtain the purpose compound.If necessary, can according to a conventional method, such as passing through the methods such as recrystallization, redeposition or chromatogram resulting purpose compound further be made with extra care.
Employed solvent is not particularly limited in the method for removing protecting group by oxidation, so long as do not hinder this reactor all can use.Such solvent can be such as ketones such as acetone; The halogenated hydrocarbons such as methylene dichloride, chloroform or tetracol phenixin; The nitriles such as acetonitrile; The ethers such as ether, tetrahydrofuran (THF) Huo diox; The amidess such as DMF, N,N-dimethylacetamide or hexamethyl phosphoric triamide; The sulfoxide types such as dimethyl sulfoxide (DMSO); Or the mixed solvent of these organic solvents and water, the mixed solvent of preferred ketone, halogenated hydrocarbon, nitrile, ethers, amides, sulfoxide type or these organic solvents and water, the more preferably mixed solvent of ketone (especially acetone), halogenated hydrocarbon (especially methylene dichloride), nitrile (especially acetonitrile), amides (especially hexamethyl phosphoric triamide), sulfoxide type (especially dimethyl sulfoxide (DMSO)) or these organic solvents and water.
Employed oxygenant can be for example Potassium Persulphate, Sodium Persulfate, ceric ammonium nitrate (CAN) or 2,3-, two chloro-5,6-dicyano-para benzoquinone (DDQ), preferred CAN or DDQ.
Temperature of reaction changes with starting compound, solvent or employed oxygenant etc., but normally 0 ℃-150 ℃, preferred 10 ℃-50 ℃.
Reaction times changes with starting compound, solvent or employed oxygenant etc., but normally 15 minutes-24 hours, preferred 30 minutes-5 hours.
React complete after, from reaction mixture, isolate according to a conventional method the purpose compound of this step.For example by removing by filter oxygenant, then steam solvent, add and the immiscible solvent of water (such as benzene, ether, ethyl acetate etc.), extract, the organic layer that contains the purpose compound washes with water, with dryings such as anhydrous magnesium sulfates, then steam solvent, obtain the purpose compound.If necessary, can according to a conventional method, such as passing through the methods such as recrystallization, redeposition or chromatogram resulting purpose compound further be made with extra care.
When hydroxyl protecting group is the silicomethane base class, the common preferably method of removing by in inert solvent, reacting with the compound that can generate fluorine anion.
Employed solvent is not particularly limited, so long as do not hinder reaction and can initial substance dissolving person all can be used.The example of such solvent is the aliphatic hydrocarbon such as hexane, hexanaphthene, heptane, solvent naphtha or sherwood oil; The aromatic hydrocarbons such as benzene, toluene or dimethylbenzene; Methylene dichloride, chloroform, tetracol phenixin, 1, the halohydrocarbon such as 2-ethylene dichloride, chlorobenzene or dichlorobenzene; The ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF), diox, glycol dimethyl ether or diglyme, preferred ethers (especially tetrahydrofuran (THF)).
The employed compound that can generate fluorine anion can be for example tetrabutylammonium fluoride, hydrofluoric acid, hydrofluoric acid-pyridine or Potassium monofluoride, the preferred fluorinated tetrabutylammonium.
Temperature of reaction changes with starting compound and reagent etc., but normally-50 ℃-100 ℃, preferred-10 ℃-50 ℃.
Reaction times changes with starting compound, reagent and temperature of reaction, but normally 5 minutes-12 hours, preferred 10 minutes-1 hour.
React complete after, from reaction mixture, isolate according to a conventional method the purpose compound of this step.For example react complete after, in reaction mixture, add entry, add again and the immiscible solvent of water (such as benzene, ether, ethyl acetate etc.), extract the purpose compound, the organic layer that extracts washes with water, with dryings such as anhydrous magnesium sulfates, then steam solvent, obtain the purpose compound.If necessary, can according to a conventional method, such as passing through the methods such as recrystallization, redeposition or chromatogram resulting purpose compound further be made with extra care.
Method B be among the method A as the compound of intermediate, i.e. general formula (Va), (Vb), (Vc) and (Vd) manufacture method of other approach of compound.
Step B1 makes R in the compound (V) 3Be the step of the compound of the general formula (Va) of hydrogen atom, it is finished by following 2 steps:
(1) make general formula (VI) compound in inert solvent, in the existence of molecular sieve (preferred powder molecular sieve 5A) or not (in the presence of preferred), with general formula (IVa) compound condensation, then
(2) resulting midbody compound is reduced with reductive agent in inert solvent.
Employed solvent is not particularly limited among the step B1 (1), so long as do not hinder reaction and can initial substance dissolving person all can be used.The example of such solvent is the aliphatic hydrocarbon such as hexane, heptane, solvent naphtha or sherwood oil; The aromatic hydrocarbons such as benzene, toluene or dimethylbenzene; The halohydrocarbon such as methylene dichloride, chloroform, tetracol phenixin, ethylene dichloride, chlorobenzene or dichlorobenzene; The ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF), diox, glycol dimethyl ether or diglyme; The ester such as methyl acetate or ethyl acetate class; The alcohols such as methyl alcohol, ethanol, propyl alcohol, 2-propyl alcohol or butanols; The amidess such as methane amide, DMF, N,N-dimethylacetamide or hexamethyl phosphoric triamide; The sulfoxide type such as dimethyl sulfoxide (DMSO) or tetramethylene sulfone, preferred halo class, ethers or aromatic hydrocarbons, more preferably ethers or aromatic hydrocarbons, more more preferably aromatic hydrocarbons (especially benzene or toluene).
Temperature of reaction changes with starting compound, solvent or employed acid, but normally 0 ℃-150 ℃, preferred 50 ℃-100 ℃.
Reaction times changes with starting compound, solvent or employed acid, but normally 5 minutes-20 hours, preferred 10 minutes-12 hours.
React complete after, from reaction mixture, isolate according to a conventional method the purpose compound of this step.For example react complete after, steam solvent, in reaction mixture, add entry, add and the immiscible solvent of water (such as benzene, ether, ethyl acetate etc.) again, extract the purpose compound, the organic layer that extracts washes with water, with dryings such as anhydrous magnesium sulfates, then steam solvent, obtain the purpose compound.If necessary, can according to a conventional method, such as passing through the methods such as recrystallization, redeposition or chromatogram resulting purpose compound further be made with extra care.
Employed solvent is not particularly limited among the step B1 (2), so long as do not hinder reaction and can initial substance dissolving person all can be used.The example of such solvent is the aliphatic hydrocarbon such as hexane, heptane, solvent naphtha or sherwood oil; The aromatic hydrocarbons such as benzene, toluene or dimethylbenzene; The halohydrocarbon such as methylene dichloride, chloroform, tetracol phenixin, ethylene dichloride, chlorobenzene or dichlorobenzene; The ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF), diox, glycol dimethyl ether or diglyme; The alcohols such as methyl alcohol, ethanol, propyl alcohol, 2-propyl alcohol or butanols; Or the mixed solvent of above-mentioned solvent, preferred halogenated hydrocarbon, ethers, alcohols or its mixed solvent, more preferably alcohols (especially methyl alcohol or ethanol).
Employed reductive agent can be the aluminum hydride compounds such as lithium aluminum hydride or diisobutylaluminium hydride; Sodium borohydride or diborane etc., preferred sodium borohydride.In addition, when using sodium borohydride as reductive agent, can be with Cerium II Chloride as catalyzer.
Temperature of reaction changes with starting compound, solvent or employed acid, but normally-50 ℃-50 ℃, preferred 0 ℃-30 ℃.
Reaction times changes with starting compound, solvent or employed acid, but normally 5 minutes-20 hours, preferred 10 minutes-12 hours.
React complete after, from reaction mixture, isolate according to a conventional method the purpose compound of this step.For example react complete after, steam solvent, in reaction mixture, add entry, and then adding and the immiscible solvent of water (such as benzene, ether, ethyl acetate etc.), extract, the organic layer that contains the purpose compound washes with water, with dryings such as anhydrous magnesium sulfates, then steam solvent, obtain the purpose compound.If necessary, can according to a conventional method, such as passing through the methods such as recrystallization, redeposition or chromatogram resulting purpose compound further be made with extra care.
Step B2 is the step of making general formula (Vb) compound.(Vb) compound is such as undefined logical formula V compound, wherein R 3Represent C 1-C 6Alkyl; By shielded hydroxyl or (C 1-C 6Alkoxyl group) C of carbonyl substituted 1-C 6Alkyl; Group shown in the general formula (II)
Figure A0081780001431
In the formula, R 7, m and n be by aforementioned definitions; C 7-C 15Aralkyl; C 1-C 6Alkyl sulphonyl; Or by (C 1-C 6Alkoxyl group) C of carbonyl substituted 1-C 6Alkyl sulphonyl, this step are by making compound (Va) in inert solvent, in the existence of alkali or do not exist under (the preferred existence), react to realize with the compound of general formula (VII).
Employed solvent is not particularly limited, so long as do not hinder reaction and can initial substance dissolving person all can be used.The example of such solvent is the aliphatic hydrocarbon such as hexane, hexanaphthene, heptane, solvent naphtha or sherwood oil; The aromatic hydrocarbons such as benzene, toluene or dimethylbenzene; Methylene dichloride, chloroform, tetracol phenixin, 1, the halohydrocarbon such as 2-ethylene dichloride, chlorobenzene or dichlorobenzene; The ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF), diox, glycol dimethyl ether or diglyme; The ketone such as acetone or methylethylketone; The nitro-compound classes such as Nitromethane 99Min.; The nitrile such as acetonitrile or isopropyl cyanide; The amidess such as methane amide, DMF, N,N-dimethylacetamide or METHYLPYRROLIDONE; Or the sulfoxide types such as dimethyl sulfoxide (DMSO) or tetramethylene sulfone, preferred halogenated hydrocarbon (especially methylene dichloride), ethers (especially ether or tetrahydrofuran (THF)) or amides (especially DMF).
Employed alkali can be alkaline carbonate classes such as yellow soda ash, salt of wormwood or Quilonum Retard; The alkali metal hydrocarbonate classes such as sodium bicarbonate, saleratus or lithium bicarbonate; The alkalimetal hydride classes such as lithium hydride, sodium hydride or potassium hydride KH; The alkali metal hydroxides such as sodium hydroxide, potassium hydroxide or lithium hydroxide; The alkali metal alcohol salts such as sodium methylate, sodium ethylate, potassium tert.-butoxide or lithium methoxide; Methylamine, dimethylamine, ethamine, triethylamine, Tributylamine, diisopropyl ethyl amine, N-methylmorpholine, pyridine, 4-(N, the N-dimethylamino) pyridine, N, accelerine, N, the N-Diethyl Aniline, 1,5-diazabicyclo [4.3.0] ninth of the ten Heavenly Stems-5-alkene, 1,4-diazabicyclo [2.2.2] octane (DABCO) or 1,8-diazabicyclo [5.4.0] 11 carbon-organic bases such as 7-alkene (DBU), preferred alkali metal carbonate class (especially yellow soda ash or salt of wormwood), alkali metal hydrocarbonate class (especially sodium bicarbonate or saleratus) or alkalimetal hydride class (especially lithium hydride or sodium hydride).
Temperature of reaction changes with starting compound and reagent etc., but normally-10 ℃-100 ℃, preferred 0 ℃-50 ℃.
Reaction times changes with starting compound, reagent and temperature of reaction, but normally 10 minutes-24 hours, preferred 1-12 hour.
React complete after, from reaction mixture, isolate according to a conventional method the purpose compound of this step.For example, react complete after, in reaction mixture, add entry, add and the immiscible solvent of water (such as benzene, ether, ethyl acetate etc.), extract the purpose compound, the organic layer that extracts washes with water, with dryings such as anhydrous magnesium sulfates, then steam solvent, obtain the purpose compound.If necessary, can according to a conventional method, such as passing through the methods such as recrystallization, redeposition or chromatogram resulting purpose compound further be made with extra care.
Step B3 makes R in the compound (V) 3Be C 1-C 6Alkyl or C 7-C 15The compound of aralkyl, it is the step of general formula (Vc) compound, this step is by making compound (Va) in inert solvent, in the presence of acetic acid and sodium cyanoborohydride or triacetoxy borohydride hydrogen sodium, reacts to realize with general formula (VIII) compound.
Employed solvent is not particularly limited, so long as do not hinder reaction and can initial substance dissolving person all can be used.The example of such solvent is the aliphatic hydrocarbon such as hexane, hexanaphthene, heptane, solvent naphtha or sherwood oil; The aromatic hydrocarbons such as benzene, toluene or dimethylbenzene; Methylene dichloride, chloroform, tetracol phenixin, 1, the halohydrocarbon such as 2-ethylene dichloride, chlorobenzene or dichlorobenzene; The ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF), diox, glycol dimethyl ether or diglyme; The alcohols such as methyl alcohol, ethanol, propyl alcohol, 2-propyl alcohol, butanols or isopropylcarbinol; The amidess such as methane amide, DMF, N,N-dimethylacetamide or METHYLPYRROLIDONE; The sulfoxide type such as dimethyl sulfoxide (DMSO) or tetramethylene sulfone; Or the mixed solvent of above-mentioned organic solvent, preferred halogenated hydrocarbon (especially methylene dichloride), alcohols (methyl alcohol or ethanol) or its mixed solvent (the especially mixed solvent of methylene dichloride and methyl alcohol).
Temperature of reaction changes with starting compound and reagent etc., but normally-10 ℃-150 ℃, preferred 0 ℃-100 ℃.
Reaction times changes with starting compound, reagent and temperature of reaction, but normally 10 minutes-24 hours, preferred 1-12 hour.
React complete after, from reaction mixture, isolate according to a conventional method the purpose compound of this step.For example, react complete after, in reaction mixture, add entry, add and the immiscible solvent of water (such as benzene, ether, ethyl acetate etc.), extract the purpose compound, the organic layer that extracts washes with water, with dryings such as anhydrous magnesium sulfates, then steam solvent, obtain the purpose compound.If necessary, can according to a conventional method, such as passing through the methods such as recrystallization, redeposition or chromatogram resulting purpose compound further be made with extra care.
Step B4 makes R in the compound (V) 3C 1-C 6Alkanoyl or the C that is replaced by shielded hydroxyl 2-C 6The compound of alkanoyl, i.e. the step of general formula (Vd) compound, this step realizes by following 2 steps:
(1) make compound (Va) in inert solvent, (preferably in the presence of alkali) and general formula (IX) or the reaction of compound (X) in the existence of alkali or not, then if desired,
(2) remove the hydroxyl protecting group in the resulting compound in above-mentioned (1).
Employed solvent is not particularly limited among the step B4 (1), so long as do not hinder reaction and can initial substance dissolving person all can be used.The example of such solvent is the aliphatic hydrocarbon such as hexane, hexanaphthene, heptane, solvent naphtha or sherwood oil; The aromatic hydrocarbons such as benzene, toluene or dimethylbenzene; Methylene dichloride, chloroform, tetracol phenixin, 1, the halohydrocarbon such as 2-ethylene dichloride, chlorobenzene or dichlorobenzene; The ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF), diox, glycol dimethyl ether or diglyme; The ketone such as acetone or methylethylketone; The nitro-compound classes such as Nitromethane 99Min.; The nitrile such as acetonitrile or isopropyl cyanide; The amidess such as methane amide, DMF, N,N-dimethylacetamide or METHYLPYRROLIDONE; Or the sulfoxide types such as dimethyl sulfoxide (DMSO) or tetramethylene sulfone, preferred halogenated hydrocarbon (especially methylene dichloride) or ethers (ether or tetrahydrofuran (THF)).
Employed alkali can be alkaline carbonate classes such as yellow soda ash, salt of wormwood or Quilonum Retard; The alkali metal hydrocarbonate classes such as sodium bicarbonate, saleratus or lithium bicarbonate; The alkali metal hydroxides such as sodium hydroxide, potassium hydroxide or lithium hydroxide; Methylamine, dimethylamine, ethamine, triethylamine, Tributylamine, diisopropyl ethyl amine, N-methylmorpholine, pyridine, 4-(N, the N-dimethylamino) pyridine, N, accelerine, N, the N-Diethyl Aniline, 1,5-diazabicyclo [4.3.0] ninth of the ten Heavenly Stems-5-alkene, 1,4-diazabicyclo [2.2.2] octane (DABCO) or 1,8-diazabicyclo [5.4.0] 11 carbon-organic bases such as 7-alkene (DBU), preferred alkali metal carbonate class (especially yellow soda ash or salt of wormwood), alkali metal hydrocarbonate class (especially sodium bicarbonate or saleratus) or organic bases (triethylamine especially, pyridine or 4-(N, N-dimethylamino) pyridine).
Temperature of reaction changes with starting compound and reagent etc., but normally-10 ℃-100 ℃, preferred 0 ℃-50 ℃.
Reaction times changes with starting compound, reagent and temperature of reaction, but normally 10 minutes-24 hours, preferred 1-12 hour.
React complete after, from reaction mixture, isolate according to a conventional method the purpose compound of this step.For example, react complete after, in reaction mixture, add entry, add and the immiscible solvent of water (such as benzene, ether, ethyl acetate etc.), extract the purpose compound, the organic layer that extracts washes with water, with dryings such as anhydrous magnesium sulfates, then steam solvent, obtain the purpose compound.If necessary, can according to a conventional method, such as passing through the methods such as recrystallization, redeposition or chromatogram resulting purpose compound further be made with extra care.
Among the step B4 (2), removing of hydroxyl protecting group can be carried out under the condition identical with the reaction (e) of steps A 2.
Method C be among the method A as the compound of intermediate, i.e. the manufacture method of other approach of compound (V).
Step C1 is the step of making compound (V), and this step is by making general formula (XI) compound in inert solvent, finishing with compound (IV) condensation in the presence of palladium catalyst and phosphines.
Employed solvent is not particularly limited, so long as do not hinder reaction and can initial substance dissolving person all can be used.The example of such solvent is the aliphatic hydrocarbon such as hexane, hexanaphthene, heptane, solvent naphtha or sherwood oil; The aromatic hydrocarbons such as benzene, toluene or dimethylbenzene; Methylene dichloride, chloroform, tetracol phenixin, 1, the halohydrocarbon such as 2-ethylene dichloride, chlorobenzene or dichlorobenzene; The ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF), diox, glycol dimethyl ether or diglyme; Or the nitriles such as acetonitrile or isopropyl cyanide, preferred ethers (especially tetrahydrofuran (THF)).
Employed palladium catalyst can be for example three (dibenzalacetones), two palladiums-chloroform complex, two (dibenzalacetone) palladium, acid chloride or π-allyl palladium chloride dimer, preferred three (dibenzalacetones), two palladiums-chloroform complex.
Employed phosphine-derivatives can be three (C such as trimethyl-phosphine, triethyl phosphine, tripropyl phosphine, tributylphosphine, three amyl group phosphines or three hexyl phosphines 1-C 6Alkyl) phosphine; Three (the C such as triphenylphosphine, three indenyl phosphines or three naphthyl phosphines 6-C 10Aryl) phosphine; Or tolyl diphenylphosphine, trimethylphenyl phosphine, three _ basic phosphine, tributyl Phenylphosphine or three (6-ethyl-2-naphthyl) phosphine etc. are with C 1-C 4Three (C of alkyl substituent 6-C 10Aryl) phosphine, preferably three (C 1-C 6Alkyl) phosphine (especially trimethyl-phosphine, triethyl phosphine, tripropyl phosphine or tributylphosphine) or three (C 6-C 10Aryl) phosphine (especially triphenylphosphine, three indenyl phosphines or three naphthyl phosphines) is more preferably tributylphosphine or triphenylphosphine, particularly preferably is triphenylphosphine.
Temperature of reaction changes with starting compound and reagent etc., but normally-10 ℃-100 ℃, preferred 0 ℃-50 ℃.
Reaction times changes with starting compound, reagent and temperature of reaction, but normally 10 minutes-10 hours, preferred 30 minutes-5 hours.
React complete after, from reaction mixture, isolate according to a conventional method the purpose compound of this step.For example, react complete after, obtain the purpose compound by steaming solvent.If necessary, can according to a conventional method, such as passing through the methods such as recrystallization, redeposition or chromatogram resulting purpose compound further be made with extra care.
Method D be among the method A as the compound of intermediate, i.e. the manufacture method of other approach of compound (V).
Step D1 is the step of making general formula (XIII) compound, this step is by making compound (III) in inert solvent, in the presence of phosphines and azo-compound, finish with general formula (XII) compound condensation, condensation reaction with the same condition of steps A 1 under carry out.
Step D2 is the step of making general formula (XIV) compound, and this step is to finish by the hydroxyl protecting group of removing in the compound (XIII), this reaction with the same condition of the reaction (e) of A2 step under carry out.
Step D3 is the step of making compound (V), this step is by making compound (XIV) in inert solvent, in the presence of phosphines and azo-compound, finish with general formula (XV) compound condensation, condensation reaction with the same condition of steps A 1 under carry out.
As the compound (III) of starting compound of the present invention, (IV), (IVa), (VI), (XI) or (XII), can be easily according to for example following method manufacturing.(method E) (method G) (method H)
Figure A0081780001501
(method J) (method K)
Figure A0081780001521
(method L)
Figure A0081780001522
(method M) (method N) (method O)
In above-mentioned reaction scheme:
R 1, R 2, R 3, R 3A, R 3B, R 3C, R 3D, R 4, R 5, R 6, R 8, R 9, R 10, R 11, R 12, R 13Press aforementioned definitions with X;
R 2A represents hydrogen atom;
R 5The a representation carboxy;
R 5B represents (C 1-C 6Alkoxyl group) carbonyl;
R 5C represents formamyl, (C 1-C 6Alkyl) formamyl or two (C 1-C 6Alkyl) formamyl;
Z representation hydroxy or leavings group.
At above-mentioned R 5" (C in the b definition 1-C 6Alkoxyl group) carbonyl ", R 5" (C in the c definition 1-C 6Alkyl) formamyl " and " two (C 1-C 6Alkyl) formamyl " implication and aforementioned R 5Middle definition identical.
" leavings group " in the Z definition is so long as can just have no particular limits as the group that nucleophilic group is left away.Its example can be the halogen atoms such as chlorine atom, bromine atoms or iodine atom; The C such as mesyloxy, ethanesulfonyloxy group, the third sulfonyloxy or fourth sulfonyloxy 1-C 4Alkane sulfonyl oxy; Trifluoro-methanesulfonyl oxy, 2,2,2-trichlorine ethanesulfonyloxy group, 3,3, the halo C such as 3-tribromo the third sulfonyloxy or 4,4,4-trifluoro fourth sulfonyloxy 1-C 4Alkane sulfonyl oxy; Or phenylsulfonyloxy, α-naphthalene sulfonyl oxygen base, β-naphthalene sulfonyl oxygen base, tolysulfonyl oxygen base, 4-tertiary butyl sulfonyloxy, mesitylene sulfonyloxy or 6-ethyl-α-naphthalene sulfonyl oxygen base etc. are optionally by 1-3 C 1-C 4The C that alkyl replaces 6-C 10Aryl sulfonyl; preferably halogen atom, mesyloxy, ethanesulfonyloxy group, trifluoro-methanesulfonyl oxy, 2; 2; 2-trichlorine ethanesulfonyloxy group, phenylsulfonyloxy, tosyloxy or mesitylene sulfonyloxy; more preferably halogen atom mesyloxy, trifluoro-methanesulfonyl oxy, phenylsulfonyloxy, tolysulfonyl oxygen base or mesitylene sulfonyloxy; also halogen atom more preferably particularly preferably is fluorine atom or chlorine atom.
Method E is compound (VI), (III) or manufacture method (XI).
Step e 1 is to make the step of compound (VI), and this step is by making general formula (XVI) compound react to finish with general formula (XVII) compound in inert solvent.
Employed solvent is not particularly limited, so long as do not hinder reaction and can initial substance dissolving person all can be used.The example of such solvent is the aliphatic hydrocarbon such as hexane, hexanaphthene, heptane, solvent naphtha or sherwood oil; The aromatic hydrocarbons such as benzene, toluene or dimethylbenzene; Methylene dichloride, chloroform, tetracol phenixin, 1, the halohydrocarbon such as 2-ethylene dichloride, chlorobenzene or dichlorobenzene; The ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF), diox, glycol dimethyl ether or diglyme; Or the nitriles such as acetonitrile, propionitrile or butyronitrile, aromatic hydrocarbons class (especially benzene or toluene).
Temperature of reaction changes with starting compound and reagent etc., but normally 0 ℃-150 ℃, preferred 30 ℃-100 ℃.
Reaction times changes with starting compound, reagent and temperature of reaction, but normally 10 minutes-10 hours, preferred 30 minutes-5 hours.
React complete after, from reaction mixture, isolate according to a conventional method the purpose compound of this step.For example, react complete after, obtain the purpose compound by steaming solvent.If necessary, can according to a conventional method, such as passing through the methods such as recrystallization, redeposition or chromatogram resulting purpose compound further be made with extra care.
Step e 2 is to make the step of compound (III), and this step is by making compound (VI) in inert solvent, also originally finishing in the presence of reductive agent.
Employed solvent is not particularly limited, so long as do not hinder reaction and can initial substance dissolving person all can be used.The example of such solvent is the aliphatic hydrocarbon such as hexane, hexanaphthene, heptane, solvent naphtha or sherwood oil; The aromatic hydrocarbons such as benzene, toluene or dimethylbenzene; Methylene dichloride, chloroform, tetracol phenixin, 1, the halohydrocarbon such as 2-ethylene dichloride, chlorobenzene or dichlorobenzene; The ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF), diox, glycol dimethyl ether or diglyme; The alcohols such as methyl alcohol, ethanol, propyl alcohol, 2-propyl alcohol, butanols or isopropylcarbinol; Or the mixed solvent of above-mentioned solvent.When reductive agent was aluminum hydride or diborane, solvent for use was aliphatic hydrocarbon (especially hexane or hexanaphthene), aromatic hydrocarbons (especially benzene, toluene or dimethylbenzene) or ethers (especially ether, tetrahydrofuran (THF) Huo diox).When reductive agent was sodium borohydride, solvent for use was the mixed solvent (the especially mixed solvent of methylene dichloride and ethanol) of alcohols (especially methyl alcohol or ethanol) or halogenated hydrocarbon and alcohols.
Employed reductive agent can be the aluminum hydride compounds such as lithium aluminum hydride or diisobutylaluminium hydride; Sodium borohydride or diborane etc., preferred sodium borohydride.In addition, when using sodium borohydride as reductive agent, can be with Cerium II Chloride as catalyzer.
Temperature of reaction changes with starting compound and reagent etc., but normally-78 ℃-100 ℃, preferred 0 ℃-50 ℃.
Reaction times changes with starting compound, reagent and temperature of reaction, but normally 10 minutes-12 hours, preferred 30 minutes-5 hours.
React complete after, from reaction mixture, isolate according to a conventional method the purpose compound of this step.For example, react complete after, steam solvent, in the gained residue, add water, and then adding and the immiscible solvent of water (such as benzene, ether, ethyl acetate etc.), extract the purpose compound, the organic layer that extracts washes with water, with dryings such as anhydrous magnesium sulfates, then steam solvent, obtain the purpose compound.If necessary, can according to a conventional method, such as passing through the methods such as recrystallization, redeposition or chromatogram resulting purpose compound further be made with extra care.
Step e 3 is to make the step of compound (XI), and this step is by making compound (III) in inert solvent, and (preferably in the presence of alkali) and general formula (XVIII) compound react to finish in the existence of alkali or not.
Employed solvent is not particularly limited, so long as do not hinder reaction and can initial substance dissolving person all can be used.The example of such solvent is the aliphatic hydrocarbon such as hexane, hexanaphthene, heptane, solvent naphtha or sherwood oil; The aromatic hydrocarbons such as benzene, toluene or dimethylbenzene; Methylene dichloride, chloroform, tetracol phenixin, 1, the halohydrocarbon such as 2-ethylene dichloride, chlorobenzene or dichlorobenzene; The ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF), diox, glycol dimethyl ether or diglyme; The ketone such as acetone or methylethylketone; The nitro-compound classes such as Nitromethane 99Min.; The nitrile such as acetonitrile or isopropyl cyanide; The amidess such as methane amide, DMF, N,N-dimethylacetamide or METHYLPYRROLIDONE; The sulfoxide type such as dimethyl sulfoxide (DMSO) or tetramethylene sulfone, preferred halogenated hydrocarbon (especially methylene dichloride) or ethers (especially ether or tetrahydrofuran (THF)).
Used alkali can be the alkaline carbonate classes such as yellow soda ash, salt of wormwood or Quilonum Retard; The alkali metal hydrocarbonate classes such as sodium bicarbonate, saleratus or lithium bicarbonate; Or triethylamine, Tributylamine, diisopropyl ethyl amine, N-methylmorpholine, pyridine, 4-(N, the N-dimethylamino) pyridine, N, accelerine, N, N-Diethyl Aniline, 1,5-diazabicyclo [4.3.0] ninth of the ten Heavenly Stems-5-alkene, 1,4-diazabicyclo [2.2.2] octane (DABCO) or 1,8-diazabicyclo [5.4.0], 11 carbon-organic bases such as 7-alkene (DBU), preferred organic amine (especially triethylamine or pyridine).
Temperature of reaction changes with starting compound and reagent etc., but normally-50 ℃-80 ℃, preferred-20 ℃-50 ℃.
Reaction times changes with starting compound, reagent and temperature of reaction, but normally 10 minutes-10 hours, preferred 30 minutes-5 hours.
React complete after, from reaction mixture, isolate according to a conventional method the purpose compound of this step.For example, react complete after, in reaction mixture, add entry, add and the immiscible solvent of water (such as benzene, ether, ethyl acetate etc.), extract the purpose compound, the organic layer that extracts washes with water, with dryings such as anhydrous magnesium sulfates, then steam solvent, obtain the purpose compound.If necessary, can according to a conventional method, such as passing through the methods such as recrystallization, redeposition or chromatogram resulting purpose compound further be made with extra care.
Method G is R in the compound (III) 2Compound for hydrogen atom.It is the manufacture method of other approach of general formula (IIIa) compound.
Step G1 is the step of making general formula (XXIV) compound, and this step is finished by following 2 steps:
(1) makes general formula (XXII) compound in inert solvent or do not have (preferably not having solvent) and the reaction of catechol borane under the condition of solvent, then
(2) make resulting midbody compound in inert solvent, in the presence of palladium catalyst and alkali, react with general formula (XXIII) compound.
Employed solvent is not particularly limited among the step G1 (1), so long as do not hinder reaction and can initial substance dissolving person all can be used.The example of such solvent is the aliphatic hydrocarbon such as hexane, hexanaphthene, heptane, solvent naphtha or sherwood oil; The aromatic hydrocarbons such as benzene, toluene or dimethylbenzene; Methylene dichloride, chloroform, tetracol phenixin, 1, the halohydrocarbon such as 2-ethylene dichloride, chlorobenzene or dichlorobenzene; The ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF), diox, glycol dimethyl ether or diglyme, preferred aliphatic series hydro carbons (especially hexane or sherwood oil) or aromatic hydrocarbons (especially toluene).
The temperature of reaction of step G1 (1) changes with starting compound and reagent etc., but normally-10 ℃-100 ℃, preferred 30 ℃-80 ℃.
Step G1 (1) reaction times changes with starting compound, reagent and temperature of reaction, but normally 10 minutes-10 hours, preferred 30 minutes-5 hours.
React complete after, the purpose compound of step G1 (1) can be separated from reaction mixture according to a conventional method.For example, react complete after, obtain the purpose compound by steaming solvent.In addition, also can be directly used in the next step without making with extra care especially.
Employed solvent is not particularly limited among the step G1 (2), so long as do not hinder reaction and can initial substance dissolving person all can be used.The example of such solvent is the aliphatic hydrocarbon such as hexane, hexanaphthene, heptane, solvent naphtha or sherwood oil; The aromatic hydrocarbons such as benzene, toluene or dimethylbenzene; Methylene dichloride, chloroform, tetracol phenixin, 1, the halohydrocarbon such as 2-ethylene dichloride, chlorobenzene or dichlorobenzene; The ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF), diox, glycol dimethyl ether or diglyme, the alcohols such as methyl alcohol, ethanol, propyl alcohol, 2-propyl alcohol, butanols or isopropylcarbinol; Or the mixed solvent of above-mentioned organic solvent, aromatic hydrocarbons class (especially toluene).
Employed palladium catalyst can be palladium phosphine compositions such as tetrakis triphenylphosphine palladium, two (triphenylphosphine) Palladous chloride title complex, two (diphenyl phosphine ferrocene) Palladous chloride title complex or two (triphenylphosphine) acid chlorides among the step G1 (2); Or three (dibenzalacetones), two palladiums-chloroform complex, two (dibenzalacetone) palladium, acid chloride or π-allyl palladium chloride dimer, preferred tetrakis triphenylphosphine palladium, two (triphenylphosphine) Palladous chloride title complex or two (diphenyl phosphine ferrocene) Palladous chloride title complex, more preferably tetrakis triphenylphosphine palladium.
Employed alkali can be alkaline carbonate classes such as yellow soda ash, salt of wormwood or Quilonum Retard among the step G1 (2); The alkali metal hydrocarbonate classes such as sodium bicarbonate, saleratus or lithium bicarbonate; The alkali metal alcoholates such as sodium methylate, sodium ethylate, potassium tert.-butoxide or lithium methoxide; Or triethylamine, Tributylamine, diisopropyl ethyl amine, N-methylmorpholine, pyridine, 4-(N, the N-dimethylamino) pyridine, N, accelerine, N, N-Diethyl Aniline, 1,5-diazabicyclo [4.3.0] ninth of the ten Heavenly Stems-5-alkene, 1,4-diazabicyclo [2.2.2] octane (DABCO) or 1,8-diazabicyclo [5.4.0], 11 carbon-organic bases such as 7-alkene (DBU), preferred as alkali alkoxide (especially sodium ethylate).
The temperature of reaction of step G1 (2) changes with starting compound and reagent etc., but normally 0 ℃-150 ℃, preferred 50 ℃-120 ℃.
The reaction times of step G1 (2) changes with starting compound, reagent and temperature of reaction, but normally 10 minutes-10 hours, preferred 30 minutes-5 hours.
React complete after, the purpose compound of step G1 (2) can be separated from reaction mixture according to a conventional method.For example, react complete after, in reaction mixture, add entry, add and the immiscible solvent of water (such as benzene, ether, ethyl acetate etc.), extract the purpose compound, the organic layer that extracts washes with water, with dryings such as anhydrous magnesium sulfates, then steam solvent, obtain the purpose compound.If necessary, can according to a conventional method, such as passing through the methods such as recrystallization, redeposition or chromatogram resulting purpose compound further be made with extra care.
Step G2 is the step of making compound (IIIa), and this step is to finish by the hydroxyl protecting group of removing in the compound (XXIV), this reaction can with the same condition of the reaction (e) of steps A 2 under carry out.
Method H is general formula (IVa), (IVb), (IVc) or (IVd) manufacture method of compound.
Step H1 is the step of making general formula (XXVI) compound, and this step can be finished through the following steps:
(1) when Z represents leavings group in general formula (XXV) compound, make compound (XXV) in inert solvent, in the presence of alkali, with compound (XV) reaction, perhaps
(2) when in general formula (XXV) compound during Z representation hydroxy, make compound (XXV) in inert solvent, in the presence of phosphines or azo-compound with compound (XV) dehydrating condensation.
Employed solvent is not particularly limited among the step H1 (1), so long as do not hinder reaction and can initial substance dissolving person all can be used.The example of such solvent is the aliphatic hydrocarbon such as hexane, hexanaphthene, heptane, solvent naphtha or sherwood oil; The aromatic hydrocarbons such as benzene, toluene or dimethylbenzene; Methylene dichloride, chloroform, tetracol phenixin, 1, the halohydrocarbon such as 2-ethylene dichloride, chlorobenzene or dichlorobenzene; The ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF), diox, glycol dimethyl ether or diglyme; The nitro-compound classes such as Nitromethane 99Min.; The nitrile such as acetonitrile or isopropyl cyanide; The amidess such as methane amide, DMF, N,N-dimethylacetamide or METHYLPYRROLIDONE; Or the sulfoxide types such as dimethyl sulfoxide (DMSO) or tetramethylene sulfone, preferred amide class (especially DMF or N,N-dimethylacetamide).
Employed alkali can be alkaline carbonate classes such as yellow soda ash, salt of wormwood or Quilonum Retard among the step H1 (1); The alkali metal hydrocarbonate classes such as sodium bicarbonate, saleratus or lithium bicarbonate; The alkali metal acetate classes such as sodium acetate; The alkalimetal hydride classes such as lithium hydride, sodium hydride or potassium hydride KH; The alkali metal hydroxides such as sodium hydroxide, potassium hydroxide or lithium hydroxide; The alkali metal alcohol salts such as sodium methylate, sodium ethylate, potassium tert.-butoxide or lithium methoxide; Triethylamine, Tributylamine, diisopropyl ethyl amine, N-methylmorpholine, pyridine, 4-(N, the N-dimethylamino) pyridine, N, accelerine, N, N-Diethyl Aniline, 1,5-diazabicyclo [4.3.0] ninth of the ten Heavenly Stems-5-alkene, 1,4-diazabicyclo [2.2.2] octane (DABCO) or 1,8-diazabicyclo [5.4.0], 11 carbon-organic bases such as 7-alkene (DBU); The lithium alkylide classes such as lithium methide, lithium ethide or butyllithium; Or the alkylamino lithiums such as diisopropylaminoethyl lithium or dicyclohexyl lithium amide, preferred as alkali hydride class (especially lithium hydride or sodium hydride), alkali metal alcohol salt (especially sodium methylate) or lithium alkylide class (especially butyllithium).
The temperature of reaction of step H1 (1) changes with starting compound and reagent etc., but normally-10 ℃-100 ℃, preferred-5 ℃-50 ℃.
The reaction times of step H1 (1) changes with starting compound, reagent and temperature of reaction, but normally 5 minutes-24 hours, preferred 10 minutes-12 hours.
React complete after, the purpose compound of step H1 (1) can be separated from reaction mixture according to a conventional method.For example, react complete after, in reaction mixture, add entry, add and the immiscible solvent of water (such as benzene, ether, ethyl acetate etc.), extract the purpose compound, the organic layer that extracts washes with water, with dryings such as anhydrous magnesium sulfates, then steam solvent, obtain the purpose compound.If necessary, can according to a conventional method, such as passing through the methods such as recrystallization, redeposition or chromatogram resulting purpose compound further be made with extra care.
Employed solvent is not particularly limited among the step H1 (2), so long as do not hinder reaction and can initial substance dissolving person all can be used.The example of such solvent is the aliphatic hydrocarbon such as hexane, heptane, solvent naphtha or sherwood oil; The aromatic hydrocarbons such as benzene, toluene or dimethylbenzene; The halohydrocarbon such as methylene dichloride, chloroform, tetracol phenixin, ethylene dichloride, chlorobenzene or dichlorobenzene; The ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF), diox, glycol dimethyl ether or diglyme, preferably aliphatic hydrocarbon, aromatic hydrocarbons, halogenated hydrocarbon or ethers are more preferably halogenated hydrocarbon (methylene dichloride) or ethers (particularly diethyl ether or tetrahydrofuran (THF)).
Employed phosphine-derivatives can be three (C such as trimethyl-phosphine, triethyl phosphine, tripropyl phosphine, tributylphosphine, three amyl group phosphines or three hexyl phosphines among the step H1 (2) 1-C 6Alkyl) phosphine; Three (the C such as triphenylphosphine, three indenyl phosphines or three naphthyl phosphines 6-C 10Aryl) phosphine; Or tolyl diphenylphosphine, trimethylphenyl phosphine, three _ basic phosphine, tributyl Phenylphosphine or three (6-ethyl-2-naphthyl) phosphine etc. are with C 1-C 4Three (C of alkyl substituent 6-C 10Aryl) phosphine, preferably three (C 1-C 6Alkyl) phosphine (especially trimethyl-phosphine, triethyl phosphine, tripropyl phosphine or tributylphosphine) or three (C 6-C 10Aryl) phosphine (especially triphenylphosphine, three indenyl phosphines or three naphthyl phosphines) is more preferably tributylphosphine or triphenylphosphine.
Employed azo-compound can be azo dicarbapentaborane two piperidines for example among the step H1 (2), or the azoformic acid two (C such as azo acid dimethyl ester, diethyl azodiformate, azoformic acid dipropyl or azoformic acid dibutylester 1-C 4Alkyl) ester, preferred azo acid dimethyl ester or diethyl azodiformate.
Temperature of reaction among the step H1 (2) changes with starting compound and reagent etc., but normally-20 ℃-100 ℃, preferred-10 ℃-50 ℃.
Reaction times among the step H1 (2) changes with starting compound, reagent and temperature of reaction, but normally 15 minutes-48 hours, preferred 30 minutes-24 hours.
React complete after, the purpose compound of step H1 (2) can be separated from reaction mixture according to a conventional method.For example, react complete after, in the situation that there is insolubles, by removing by filter insolubles, then steam solvent, in the residue that steams behind the solvent, add water, and then adding and the immiscible solvent of water (such as benzene, ether, ethyl acetate etc.), extract, the organic layer that contains the purpose compound washes with water, with dryings such as anhydrous magnesium sulfates, then steam solvent, obtain the purpose compound.If necessary, can according to a conventional method, such as passing through the methods such as recrystallization, redeposition or chromatogram resulting purpose compound further be made with extra care.
Step H2 is the step of making compound (IVa), and this step is finished through the following steps:
(1) in inert solvent, in the atmosphere of hydrogen of 1-5 normal atmosphere (preferred 1 normal atmosphere), makes compound (XXVI) reduction with catalytic reduction catalysts, perhaps
(2) adopt the amino method of known nitroreduction one-tenth in the organic chemistry, for example in the presence of metal powder, compound (XXVI) is stirred in acetic acid, make it reduction.
Employed solvent is not particularly limited in the catalytic reduction, so long as do not hinder reaction and can initial substance dissolving person all can be used.The example of such solvent is the aliphatic hydrocarbon such as hexane, hexanaphthene, heptane, solvent naphtha or sherwood oil; The aromatic hydrocarbons such as benzene, toluene or dimethylbenzene; Methylene dichloride, chloroform, tetracol phenixin, 1, the halohydrocarbon such as 2-ethylene dichloride, chlorobenzene or dichlorobenzene; The ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF), diox, glycol dimethyl ether or diglyme; The alcohols such as methyl alcohol, ethanol, propyl alcohol, 2-propyl alcohol, butanols or isopropylcarbinol; Or its mixed solvent, the mixed solvent (the especially mixed solvent of tetrahydrofuran (THF) and methyl alcohol or ethanol) of preferred alcohols (especially methyl alcohol) or ethers and alcohols.
Employed catalyzer is not particularly limited in the catalytic reduction reaction, all can use as long as can be used for common catalytic reduction reaction person.The example of this catalyzer can be that for example palladium black, palladium charcoal, palladium hydroxide, charcoal carry palladium hydroxide, Raney nickel, rhodium-aluminum oxide, palladium-barium sulfate, platinum oxide or platinum black, preferred palladium charcoal.
Temperature of reaction changes with starting compound and reagent etc., but normally-10 ℃-100 ℃, preferred 0 ℃-50 ℃.
Reaction times changes with starting compound, reagent and temperature of reaction, but normally 10 minutes-10 hours, preferred 30 minutes-6 hours.
React complete after, from reaction mixture, isolate according to a conventional method the purpose compound of this step.For example, react complete after, by removing by filter catalyzer, with the concentrated purpose compound that obtains of filtrate.If necessary, can according to a conventional method, such as passing through the methods such as recrystallization, redeposition or chromatogram resulting purpose compound further be made with extra care.
Employed solvent can be the mixture of acetic acid, hydrochloric acid, water, alcohol or water-soluble organic solvent for example in the reduction reaction of carrying out with metal powder, preferred acetic acid.
Employed metal powder can be for example zinc powder, glass putty or iron powder, preferred zinc powder or glass putty.
Temperature of reaction changes with starting compound and reagent etc., but normally-10 ℃-100 ℃, preferred 0 ℃-50 ℃.
Reaction times changes with starting compound, reagent and temperature of reaction, but normally 10 minutes-10 hours, preferred 30 minutes-3 hours.
React complete after, from reaction mixture, isolate according to a conventional method the purpose compound of this step.For example, react complete after, by removing by filter catalyzer, with the concentrated purpose compound that obtains of filtrate.If necessary, can according to a conventional method, such as passing through the methods such as recrystallization, redeposition or chromatogram resulting purpose compound further be made with extra care.
Step H3 is the step of making general formula (IVb) compound, this step is by making compound (IVa) in inert solvent, (preferably in the presence of alkali) and compound (VII) reaction are not finished in the existence of alkali or, and this reaction can be carried out under the condition identical with step B2.
Step H4 is the step of making general formula (IVc) compound, this step is by making compound (IVa) in inert solvent, in the presence of acetic acid and sodium cyanoborohydride, finish with compound (VIII) reaction, this reaction can with the similarity condition of step B3 under carry out.
Step H5 is the step of making general formula (IVd) compound, and this step is finished through the following steps:
(1) make compound (IVa) in inert solvent, (preferably in the presence of alkali) and compound (IX) or (X) reaction in the existence of alkali or not, then, if desired,
(2) remove hydroxyl protecting group in the compound that obtains in above-mentioned (1), reaction conditions is identical with the condition of the reaction (e) of step B4 (1) or steps A 2.
Method J is general formula (XIIa), (XIIb), (XIIc) or (XIId) manufacture method of compound.
Step J1 is the step of making general formula (XXVII) compound, and this step can be finished through the following steps, and making the middle Z of compound (XXV) is the compound of hydroxyl, i.e. general formula (XXVa) compound.
(1) in inert solvent, in the existence of alkali or not (preferably in the presence of alkali), with general formula R 12-Za or R 12A-O-R 12The reaction of compound shown in a, R in the formula 12Implication as hereinbefore, Za represents the leavings group that defines among the Z, R 12A represents R 12The acyl group of middle definition, or
(2) in inert solvent, in the presence of condensing agent and in the existence of alkali or not (preferably in the presence of alkali), with general formula R 12Compound reaction shown in the a-OH, R in the formula 12The implication of a as hereinbefore, or
(3) in inert solvent, in the presence of the halophosphoric acid dialkyl esters such as phosphorus chloride diethyl phthalate and alkali, with general formula R 12Compound reaction shown in the a-OH, R in the formula 12The implication of a as hereinbefore, perhaps
(4) in inert solvent, in the existence of acid or not (preferably in the presence of acid), with dihydrofuran or dihydropyrans reaction.
Employed solvent is not particularly limited among the step J1 (1), so long as do not hinder reaction and can initial substance dissolving person all can be used.The example of such solvent is the aliphatic hydrocarbon such as hexane, hexanaphthene, heptane, solvent naphtha or sherwood oil; The aromatic hydrocarbons such as benzene, toluene or dimethylbenzene; Methylene dichloride, chloroform, tetracol phenixin, 1, the halohydrocarbon such as 2-ethylene dichloride, chlorobenzene or dichlorobenzene; The ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF), diox, glycol dimethyl ether or diglyme; The ester classes such as ethyl formate, ethyl acetate, propyl acetate, butylacetate or diethyl carbonate; The ketone such as acetone or methylethylketone; The nitro-compound classes such as Nitromethane 99Min.; The nitrile such as acetonitrile or isopropyl cyanide; The alcohols such as methyl alcohol, ethanol, propyl alcohol, 2-propyl alcohol, butanols or isopropylcarbinol; The amidess such as methane amide, DMF, N,N-dimethylacetamide or METHYLPYRROLIDONE; The sulfoxide type such as dimethyl sulfoxide (DMSO) or tetramethylene sulfone, preferred halogenated hydrocarbon (especially methylene dichloride), ethers (especially ether or tetrahydrofuran (THF)) or amides (especially DMF).
Employed alkali can be alkaline carbonate classes such as yellow soda ash, salt of wormwood or Quilonum Retard among the step J1 (1); The alkali metal hydrocarbonate classes such as sodium bicarbonate, saleratus or lithium bicarbonate; The alkalimetal hydride classes such as lithium hydride, sodium hydride or potassium hydride KH; The alkali metal alcoholates such as sodium methylate, sodium ethylate, potassium tert.-butoxide or lithium methoxide; Or triethylamine, Tributylamine, diisopropyl ethyl amine, N-methylmorpholine, pyridine, 4-(N, the N-dimethylamino) pyridine, N, accelerine, N, N-Diethyl Aniline, 1,5-diazabicyclo [4.3.0] ninth of the ten Heavenly Stems-5-alkene, 1,4-diazabicyclo [2.2.2] octane (DABCO) or 1,8-diazabicyclo [5.4.0] 11 carbon-organic bases such as 7-alkene (DBU), preferred as alkali hydride class (especially sodium hydride), alkali metal alcohol salt (especially potassium tert.-butoxide) or organic amine (especially triethylamine or pyridine).
In addition, can use 4-(N, the N-dimethylamino) pyridine of catalytic amount or the combination of 4-pyrrolidyl pyridine and other alkali.In addition, effectively carry out in order to make reaction, can add the quaternary ammonium salts such as benzyltriethylammoinium chloride or TBAC tetrabutylammonium chloride, or the crown ether compound such as dibenzo-18-crown-6 (DB18C6).
The temperature of reaction of step J1 (1) changes with starting compound and reagent etc., but normally-20 ℃-100 ℃, preferred 0 ℃-50 ℃.
The reaction times of step J1 (1) changes with starting compound, reagent and temperature of reaction, but normally 10 minutes-24 hours, preferred 30 minutes-12 hours.
As general formula R 12The object lesson of compound shown in the-Za can be enumerated acyl halide classes such as Acetyl Chloride 98Min., propionyl chloride, butyryl chloride, valeryl chloride, caproyl chloride, methoxycarbonyl chlorine, methoxycarbonyl bromine, ethoxycarbonyl chlorine, the third oxygen carbonyl chlorine, butoxy carbonyl chlorine, own oxygen carbonyl chlorine, Benzoyl chloride, benzoyl bromide or naphthoyl chloride; Silyl halide class or the corresponding triflate classes such as tert-butyldimethylsilyl chloride, trimethylsilyl chloride, triethylsilyl chloride, triethylsilyl bromine, triisopropyl silyl chloride, dimethyl sec.-propyl silyl chloride, diethyl sec.-propyl silyl chloride, diphenyl methyl silyl chloride, triphenyl silyl chloride; The aralkyl such as benzyl chloride, bromotoluene halogen class; Or the alkyl halide classes such as methoxymethyl chlorine, ethoxyl methyl chlorine, oxy acid methyl neopentyl chlorine or ethoxy carbonyl oxy-methyl chlorine, preferred alkyl halogenide class (especially methoxymethyl chlorine).
As general formula R 12A-O-R 12The object lesson of compound shown in a can be enumerated aliphatic carboxylic acid acid anhydrides such as diacetyl oxide, propionic anhydride, valeric anhydride or caproic anhydride, in addition, can use mixed acid anhydride, such as the mixed acid anhydride of formic acid and acetic acid.
Employed solvent is not particularly limited among the step J1 (2), so long as do not hinder reaction and can initial substance dissolving person all can be used.The example of such solvent is the aliphatic hydrocarbon such as hexane, hexanaphthene, heptane, solvent naphtha or sherwood oil; The aromatic hydrocarbons such as benzene, toluene or dimethylbenzene; Methylene dichloride, chloroform, tetracol phenixin, 1, the halohydrocarbon such as 2-ethylene dichloride, chlorobenzene or dichlorobenzene; The ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF), diox, glycol dimethyl ether or diglyme; The ketone such as acetone or methylethylketone; The nitro-compound classes such as Nitromethane 99Min.; The nitrile such as acetonitrile or isopropyl cyanide; The amidess such as methane amide, DMF, N,N-dimethylacetamide or METHYLPYRROLIDONE; The sulfoxide type such as dimethyl sulfoxide (DMSO) or tetramethylene sulfone, preferred ethers (especially ether or tetrahydrofuran (THF)) or amides (especially N,N-dimethylacetamide or METHYLPYRROLIDONE).
Employed condensing agent can be dicyclohexyl carbodiimide, carbonyl dimidazoles or 1-methyl-2-chloro-iodate pyridine-triethylamine for example among the step J1 (2), preferred dicyclohexyl carbodiimide.
Among the step J1 (2) employed alkali can enumerate with step J1 (1) in employed those identical alkali.
Temperature of reaction among the step J1 (2) changes with starting compound and reagent etc., but normally-20 ℃-100 ℃, preferred 0 ℃-50 ℃.
Reaction times among the step J1 (2) changes with starting compound, reagent and temperature of reaction, but normally 10 minutes-24 hours, preferred 30 minutes-12 hours.
Employed solvent is not particularly limited among the step J1 (3), so long as do not hinder reaction and can initial substance dissolving person all can be used.The example of such solvent is the aliphatic hydrocarbon such as hexane, hexanaphthene, heptane, solvent naphtha or sherwood oil; The aromatic hydrocarbons such as benzene, toluene or dimethylbenzene; Methylene dichloride, chloroform, tetracol phenixin, 1, the halohydrocarbon such as 2-ethylene dichloride, chlorobenzene or dichlorobenzene; The ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF), diox, glycol dimethyl ether or diglyme; The ketone such as acetone or methylethylketone; The ester classes such as ethyl formate, ethyl acetate, propyl acetate, butylacetate or diethyl carbonate; The nitro-compound classes such as Nitromethane 99Min.; The nitrile such as acetonitrile or isopropyl cyanide; The amidess such as methane amide, DMF, N,N-dimethylacetamide or METHYLPYRROLIDONE; Or the sulfoxide types such as dimethyl sulfoxide (DMSO) or tetramethylene sulfone, preferred ethers (especially ether or tetrahydrofuran (THF)).
Among the step J1 (3) employed alkali can enumerate with step J1 (1) in employed those identical alkali.
The temperature of reaction of step J1 (3) changes with starting compound and reagent etc., but normally-20 ℃-100 ℃, preferred 0 ℃-50 ℃.
The reaction times of step J1 (3) changes with starting compound, reagent and temperature of reaction, but normally 10 minutes-24 hours, preferred 30 minutes-12 hours.
Employed solvent is not particularly limited among the step J1 (4), so long as do not hinder reaction and can initial substance dissolving person all can be used.The example of such solvent is the aliphatic hydrocarbon such as hexane, hexanaphthene, heptane, solvent naphtha or sherwood oil; The aromatic hydrocarbons such as benzene, toluene or dimethylbenzene; Methylene dichloride, chloroform, tetracol phenixin, 1, the halohydrocarbon such as 2-ethylene dichloride, chlorobenzene or dichlorobenzene; The ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF), diox, glycol dimethyl ether or diglyme; The ester classes such as ethyl formate, ethyl acetate, propyl acetate, butylacetate or diethyl carbonate; The nitro compound classes such as Nitromethane 99Min.; The perhaps nitrile such as acetonitrile or isopropyl cyanide, preferred halogenated hydrocarbon (especially methylene dichloride) or ethers (especially ether or tetrahydrofuran (THF)).
Employed acid can be mineral acids such as hydrofluoric acid, hydrochloric acid, Hydrogen bromide, hydroiodic acid HI, nitric acid, perchloric acid, sulfuric acid or phosphoric acid among the step J1 (4); The sulfonic acid such as methylsulfonic acid, trifluoromethanesulfonic acid, ethyl sulfonic acid, Phenylsulfonic acid or tosic acid; Perhaps carboxylic acids such as acetic acid, propionic acid, butyric acid, fumaric acid, succsinic acid, citric acid, tartrate, oxalic acid, toxilic acid or phenylformic acid, preferred sulfonic acid (especially tosic acid).
The temperature of reaction of step J1 (4) changes with starting compound and reagent etc., but normally-20 ℃-100 ℃, preferred 0 ℃-50 ℃.
The reaction times of step J1 (4) changes with starting compound, reagent and temperature of reaction, but normally 10 minutes-24 hours, preferred 30 minutes-12 hours.
React complete after, each purpose compound of step J1 can be separated from reaction mixture according to a conventional method.For example, react complete after, in reaction mixture, add entry, add and the immiscible solvent of water (such as benzene, ether, ethyl acetate etc.), extract the purpose compound, the organic layer that extracts washes with water, with dryings such as anhydrous magnesium sulfates, then steam solvent, obtain the purpose compound.If necessary, can according to a conventional method, such as passing through the methods such as recrystallization, redeposition or chromatogram resulting purpose compound further be made with extra care.
Step J2 is the step of making compound (XIIa), and this step can be finished through the following steps:
(1) in inert solvent, in the atmosphere of hydrogen of 1-5 normal atmosphere (preferred 1 normal atmosphere), with catalytic reduction catalysts compound (XXVII) is reduced, perhaps
(2) adopt the amino method of known nitroreduction one-tenth in the organic chemistry, for example in the presence of metal powder, compound (XXVII) is stirred in acetic acid, make it reduction, its condition can be identical with the condition of step H2.
Step J3 is the step of making general formula (XIIb) compound, this step is by making compound (XIIa) in inert solvent, (preferably in the presence of alkali) and compound (VII) reaction are not finished in the existence of alkali or, and reaction conditions can be identical with the condition of step B2.
Step J4 is the step of making general formula (XIIc) compound, this step is by making compound (XIIc) in inert solvent, in the presence of acetic acid and sodium cyanoborohydride, finish with compound (VIII) reaction, this reaction can with the similarity condition of step B3 under carry out.
Step J5 is the step of making general formula (XIId) compound, and this step is finished through the following steps:
(1) make compound (XIIa) in inert solvent, (preferably in the presence of alkali) and compound (IX) or (X) reaction in the existence of alkali or not, then, if desired,
(2) remove hydroxyl protecting group in the compound that obtains in above-mentioned (1), reaction conditions is identical with the condition of the reaction (e) of step B4 (1) or steps A 2.
Method K is general formula (XXVc) or (XXVd) manufacture method of compound.
Step K 1 is to make the step of compound (XXVc), and this step is finished through the following steps: make compound (XXVb)
(1) in inert solvent, in the presence of esterifying agent, react with alcohol, or
(2) in inert solvent, with the active esterifying agent reaction, generate active ester, and then it is reacted with alcohol in inert solvent, or
(3) in inert solvent, with the halogenating agent reaction, generate carboxylic acid halides, and then it is reacted with alcohol in inert solvent, perhaps
(4) in inert solvent or under the condition that does not have solvent, (preferably there is not solvent), in the presence of acid, reacts with alcohol.
Employed esterifying agent in the step K 1 so long as in the general Synthetic Organic Chemistry technology normally used those, just be not particularly limited.Its example can be for example diazonium paraffinic hydrocarbons or trialkylsilkl diazonium paraffinic hydrocarbons, the C such as preferred diazomethane, diazoethane, diazonium propane, diazonium butane or diazonium hexane 1-C 6Diazonium paraffinic hydrocarbons or trimethyl silyl diazomethane, more preferably C 1-C 4Diazonium paraffinic hydrocarbons or trimethyl silyl diazomethane, particularly preferably diazomethane.
Using C 1-C 6Employed solvent is not particularly limited in the reaction of diazonium paraffinic hydrocarbons, so long as do not hinder reaction and can initial substance dissolving person all can be used.The example of such solvent is the aliphatic hydrocarbon such as hexane, heptane, solvent naphtha or sherwood oil; The aromatic hydrocarbons such as benzene, toluene or dimethylbenzene; The halohydrocarbon such as methylene dichloride, chloroform, tetracol phenixin, ethylene dichloride, chlorobenzene or dichlorobenzene; The ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF), diox, glycol dimethyl ether or diglyme; The ester such as methyl acetate or ethyl acetate class; The perhaps mixed solvent of above-mentioned solvent, the mixed solvent of preferred halogenated hydrocarbon, ethers, ester class or above-mentioned solvent, the more preferably mixed solvent of ethers (especially ether), ester class (especially ethyl acetate) or above-mentioned solvent.
Employed solvent is not particularly limited in the reaction of using the trimethyl silyl diazomethane, so long as do not hinder reaction and can initial substance dissolving person all can be used.The example of such solvent is the alcohols such as methyl alcohol, ethanol, propyl alcohol, 2-propyl alcohol, butanols, isopropylcarbinol, the trimethyl carbinol, amylalcohol or hexanol; Perhaps from aliphatic hydrocarbon such as hexane, heptane, solvent naphtha or sherwood oils; The aromatic hydrocarbons such as benzene, toluene or dimethylbenzene; The halohydrocarbon such as methylene dichloride, chloroform, tetracol phenixin, ethylene dichloride, chlorobenzene or dichlorobenzene; The ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF), diox, glycol dimethyl ether or diglyme; And the solvent and the mixed solvent of above-mentioned alcohols selected in the ester classes such as methyl acetate or ethyl acetate form a group, the preferably mixed solvent of alcohols (especially methyl alcohol) or aromatic hydrocarbons (especially benzene) and alcohols (especially methyl alcohol).
The temperature of reaction of step K 1 (1) changes with starting compound and reagent etc., but normally-10 ℃-100 ℃, preferred 10 ℃-50 ℃.
The reaction times of step K 1 (1) changes with starting compound, reagent and temperature of reaction, but normally 10 minutes-10 hours, preferred 15 minutes-2 hours.
React complete after, the purpose compound of step K 1 (1) can be separated from reaction mixture according to a conventional method.For example, react complete after, obtain the purpose compound by steaming solvent.If necessary, can according to a conventional method, such as passing through the methods such as recrystallization, redeposition or chromatogram resulting purpose compound further be made with extra care.
Employed active esterifying agent in the step K 1 (2) so long as in the general Synthetic Organic Chemistry technology normally used those, just be not particularly limited.Its example can be for example Vinyl chloroformate, N-hydroxy-succinamide, I-hydroxybenzotriazole or N-hydroxyl-5-norbornylene-2, the di-sulphide compounds such as the N-oxy-compound such as 3-dicarboximide or pyridyl disulfide.Active esterification is preferably carried out in the presence of the condensing agents such as dicyclohexyl carbodiimide, carbonyl dimidazoles or triphenylphosphine.
The solvent that hexane uses in 2 reactions of step K 1 (2) is not particularly limited, so long as do not hinder reaction and can initial substance dissolving person all can be used.The example of such solvent is the halogenated hydrocarbons such as methylene dichloride, chloroform, tetracol phenixin, ethylene dichloride, chlorobenzene or dichlorobenzene; The ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF), diox, glycol dimethyl ether or diglyme; The amidess such as methane amide, DMF, N,N-dimethylacetamide or hexamethyl phosphoric triamide; The perhaps nitrile such as acetonitrile, preferred ethers (especially tetrahydrofuran (THF)) or amides (especially DMF).
The temperature of reaction of step K 1 (2) changes with starting compound and reagent etc., but normally, in active esterification, temperature of reaction is-70 ℃-150 ℃ (preferred-10 ℃-100 ℃), in the reaction of active ester compound and alcohol, temperature of reaction is-20 ℃-100 ℃ (preferred 0 ℃-50 ℃).
The reaction times of step K 1 (2) changes with starting compound, reagent and temperature of reaction, but normally, in 2 reactions, the reaction times is 30 minutes-80 hours (preferred 1-48 hour).
React complete after, the purpose compound of step K 1 (2) can be separated from reaction mixture according to a conventional method.For example, react complete after, by steaming solvent, or in the residue that steams behind the solvent, add water, and add and the immiscible solvent of water (such as benzene, ether, ethyl acetate etc.) again, extract the purpose compound, the organic layer that extracts washes with water, with dryings such as anhydrous magnesium sulfates, then steam solvent, obtain the purpose compound.If necessary, can according to a conventional method, such as passing through the methods such as recrystallization, redeposition or chromatogram resulting purpose compound further be made with extra care.
In the step K 1 (3) institute use halogenating agent so long as generally in the Synthetic Organic Chemistry technology normally used those, just be not particularly limited.Its example can be for example oxalyl chloride, thionyl chloride, phosphoryl chloride or phosphorus pentachloride.
Employed solvent is not particularly limited in 2 reactions of step K 1 (3), so long as do not hinder reaction and can initial substance dissolving person all can be used.The example of such solvent is the aromatic hydrocarbons such as benzene, toluene or dimethylbenzene; Halogenated hydrocarbon or the ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF), diox, glycol dimethyl ether or diglyme such as methylene dichloride, chloroform, tetracol phenixin, ethylene dichloride, chlorobenzene or dichlorobenzene, preferred ethers (especially tetrahydrofuran (THF)).
The temperature of reaction of step K 1 (3) changes with starting compound and reagent etc., but normally, in the carboxylic acid halides reaction, temperature of reaction is-70 ℃-150 ℃ (preferred-10 ℃-100 ℃), in the reaction of carboxylic acid halides and alcohol, temperature of reaction is-20 ℃-100 ℃ (preferred 0 ℃-50 ℃).
The reaction times of step K 1 (3) changes with starting compound, reagent and temperature of reaction, but normally, in 2 reactions, the reaction times is 30 minutes-80 hours (preferred 1-48 hour).
React complete after, the purpose compound of step K 1 (3) can be separated from reaction mixture according to a conventional method.For example, react complete after, by steaming solvent, or in the residue that steams behind the solvent, add water, and add and the immiscible solvent of water (such as benzene, ether, ethyl acetate etc.) again, extract the purpose compound, the organic layer that extracts washes with water, with dryings such as anhydrous magnesium sulfates, then steam solvent, obtain the purpose compound.If necessary, can according to a conventional method, such as passing through the methods such as recrystallization, redeposition or chromatogram resulting purpose compound further be made with extra care.
The solvent that hexane uses in the step K 1 (4) is not particularly limited, so long as do not hinder reaction and can initial substance dissolving person all can be used.The example of such solvent is the halogenated hydrocarbons such as methylene dichloride, chloroform, tetracol phenixin, ethylene dichloride, chlorobenzene or dichlorobenzene; The ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF), diox, glycol dimethyl ether or diglyme; The amidess such as methane amide, DMF, N,N-dimethylacetamide or hexamethyl phosphoric triamide; The perhaps nitrile such as acetonitrile, preferred ethers (especially diethyl ether or tetrahydrofuran (THF)).
Employed acid can be mineral acids such as hydrofluoric acid, hydrochloric acid, Hydrogen bromide, hydroiodic acid HI, nitric acid, perchloric acid, sulfuric acid or phosphoric acid in the step K 1 (4); The sulfonic acid such as methylsulfonic acid, trifluoromethanesulfonic acid, ethyl sulfonic acid, Phenylsulfonic acid or tosic acid; Perhaps carboxylic acids such as acetic acid, propionic acid, butyric acid, fumaric acid, succsinic acid, citric acid, tartrate, oxalic acid, toxilic acid or phenylformic acid, preferred mineral acid (especially hydrochloric acid or sulfuric acid).
The temperature of reaction of step K 1 (4) changes with starting compound and reagent etc., but normally 0 ℃-150 ℃ (preferred 30 ℃-100 ℃).
The reaction times of step K 1 (4) changes with starting compound, reagent and temperature of reaction, but normally 30 minutes-80 hours (preferred 1-48 hour).
React complete after, the purpose compound of step K 1 (4) can be separated from reaction mixture according to a conventional method.For example, react complete after, by steaming solvent, or in the residue that steams behind the solvent, add water, and add and the immiscible solvent of water (such as benzene, ether, ethyl acetate etc.) again, extract the purpose compound, the organic layer that extracts washes with water, with dryings such as anhydrous magnesium sulfates, then steam solvent, obtain the purpose compound.If necessary, can according to a conventional method, such as passing through the methods such as recrystallization, redeposition or chromatogram resulting purpose compound further be made with extra care.
Step K 2 is to make the step of compound (XXVd), and this step is by making compound (XXVc) in inert solvent, in the existence of alkali or not (preferably in the presence of alkali), with Ammonia, C 1-C 6Alkylamine or two (C 1-C 6Alkyl) amine reacts to finish.
Employed solvent is not particularly limited, so long as do not hinder reaction and can initial substance dissolving person all can be used.The example of such solvent is the aliphatic hydrocarbon such as hexane, heptane, solvent naphtha or sherwood oil; The aromatic hydrocarbons such as benzene, toluene or dimethylbenzene; The halohydrocarbon such as methylene dichloride, chloroform, tetracol phenixin, ethylene dichloride, chlorobenzene or dichlorobenzene; The ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF), diox, glycol dimethyl ether or diglyme; The alcohols such as methyl alcohol, ethanol, propyl alcohol, 2-propyl alcohol, butanols or isopropylcarbinol; The amidess such as methane amide, DMF, N,N-dimethylacetamide, hexamethyl phosphoric triamide or hexamethyl tricresyl phosphite acid amides; The perhaps sulfoxide type such as dimethyl sulfoxide (DMSO) or tetramethylene sulfone, preferred halogenated hydrocarbon or ether, more preferably ethers (especially tetrahydrofuran (THF)).
Employed alkali can be alkaline carbonate classes such as yellow soda ash, salt of wormwood or Quilonum Retard; The alkali metal hydrocarbonate classes such as sodium bicarbonate, saleratus or lithium bicarbonate; Or the alkali metal hydroxides such as sodium hydroxide, potassium hydroxide or lithium hydroxide, preferred alkali metal carbonate (especially yellow soda ash or salt of wormwood).
Employed Ammonia can be for example ammonia or strong aqua, preferred ammoniacal liquor.
Employed C 1-C 6Alkylamine is for example methylamine, ethamine, propylamine, Isopropylamine, butylamine, isobutylamine, sec-butylamine, TERTIARY BUTYL AMINE, amylamine or hexylamine.
Employed two (C 1-C 6Alkyl) amine is N for example, N-dimethyl amine, N-ethyl-N-methylamine, N, N-diethylamide, N, N-dipropylamine, N, N-diisopropylamine, N, N-dibutylamine, N, N-diisobutyl amine, N, N-di-sec-butyl amine, N, N-di-t-butyl amine, N, N-diamyl amine or N, N-dihexyl amine.
Temperature of reaction changes with starting compound and reagent etc., but normally-10 ℃-100 ℃, preferred 0 ℃-50 ℃.
Reaction times changes with starting compound, reagent and temperature of reaction, but normally 10 minutes-10 hours, preferred 30 minutes-3 hours.
React complete after, from reaction mixture, isolate according to a conventional method the purpose compound of this step.For example, react complete after, by steaming solvent, or in the residue that steams behind the solvent, add water, and add and the immiscible solvent of water (such as benzene, ether, ethyl acetate etc.) again, extract the purpose compound, the organic layer that extracts washes with water, with dryings such as anhydrous magnesium sulfates, then steam solvent, obtain the purpose compound.If necessary, can according to a conventional method, such as passing through the methods such as recrystallization, redeposition or chromatogram resulting purpose compound further be made with extra care.
Step K 3 is steps that other approach is made compound (XXVd), this step can be undertaken by known method in the Synthetic Organic Chemistry technology, the method of commonly using in for example synthesizing according to peptide (for example trinitride method, active ester method, mixed anhydride method or condensation method (preferred mixed anhydride method)), by making compound (XXVb) in inert solvent, with Ammonia, C 1-C 6Alkylamine or two (C 1-C 6Alkyl) amine reacts to finish.
In the trinitride method of aforesaid method, make compound (XXVb) at inert solvent (for example methane amide, N, dinethylformamide, N, N-N,N-DIMETHYLACETAMIDE or hexamethyl phosphoric triamide) etc. amides, preferably in (DMF), at-10 ℃-100 ℃ (preferred 0 ℃-50 ℃) and hydrazine reaction, resulting hydrazides and nitrous compound reaction are transformed into triazo-compound, then use Ammonia, C 1-C 6Alkylamine or two (C 1-C 6Alkyl) amine is processed.
Employed nitrous compound is such as alkyl nitrites such as the alkali metal nitrites salts such as Sodium Nitrite or Isopentyl nitrites.
This reaction is preferably carried out in inert solvent.Employed solvent can be amidess such as methane amide, DMF, N,N-dimethylacetamide or hexamethyl phosphoric triamide; The sulfoxide type such as dimethyl sulfoxide (DMSO) or tetramethylene sulfone; The perhaps pyrrolidinone compounds such as METHYLPYRROLIDONE, preferred amide class (especially DMF).
2 steps of this reaction, namely azido reaction and with Ammonia, C 1-C 6Alkylamine or two (C 1-C 6Alkyl) reaction of amine is carried out in one pot usually.
Temperature of reaction changes with starting compound and reagent etc., in the azide step, temperature of reaction is-70 ℃-50 ℃ (preferred-50 ℃-0 ℃) but normally,, with the reaction of Ammonia etc. in, temperature of reaction is-70 ℃-50 ℃ (preferred-10 ℃-10 ℃).
Reaction times changes with starting compound, reagent and temperature of reaction, in the azide step, the reaction times is 5 minutes-3 hours (preferred 10 minutes-1 hour) but normally,, with the reaction of Ammonia etc. in, temperature of reaction is 5 hours-7 days (preferred 10 hours-5 days).
React complete after, from reaction mixture, isolate according to a conventional method the purpose compound of this reaction.For example, react complete after, by steaming solvent, or in the residue that steams behind the solvent, add water, and add and the immiscible solvent of water (such as benzene, ether, ethyl acetate etc.) again, extract the purpose compound, the organic layer that extracts washes with water, with dryings such as anhydrous magnesium sulfates, then steam solvent, obtain the purpose compound.If necessary, can according to a conventional method, such as passing through the methods such as recrystallization, redeposition or chromatogram resulting purpose compound further be made with extra care.
In active ester method, make compound (XXVb) in inert solvent with active esterifying agent reaction, generate active ester, then in inert solvent with Ammonia, C 1-C 6Alkylamine or two (C 1-C 6Alkyl) amine reaction.
The solvent that hexane uses in these 2 reactions is not particularly limited, so long as do not hinder reaction and can initial substance dissolving person all can be used.The example of such solvent is the halogenated hydrocarbons such as methylene dichloride, chloroform, tetracol phenixin, ethylene dichloride, chlorobenzene or dichlorobenzene; The ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF), diox, glycol dimethyl ether or diglyme; The amidess such as methane amide, DMF, N,N-dimethylacetamide or hexamethyl phosphoric triamide; The perhaps nitrile such as acetonitrile, preferred ethers (especially tetrahydrofuran (THF)) or amides (especially DMF).
Employed active esterifying agent can be for example N-hydroxy-succinamide, I-hydroxybenzotriazole or N-hydroxyl-5-norbornylene-2, the di-sulphide compounds such as the N-oxy-compound such as 3-dicarboximide or pyridyl disulfide.Active esterification is preferably carried out in the presence of the condensing agents such as dicyclohexyl carbodiimide, carbonyl dimidazoles or triphenylphosphine.
Temperature of reaction changes with starting compound and reagent etc., in active esterification, temperature of reaction is-70 ℃-150 ℃ (preferred-10 ℃-100 ℃) but normally,, in the reaction of active ester compound and Ammonia etc., temperature of reaction is-20 ℃-100 ℃ (preferred 0 ℃-50 ℃).
The needed reaction times changes with starting compound, reagent and temperature of reaction, but normally, the reaction times of 2 reactions is 30 minutes-80 hours (preferred 1-48 hours).
React complete after, from reaction mixture, isolate according to a conventional method the purpose compound of this reaction.For example, react complete after, by steaming solvent, or in the residue that steams behind the solvent, add water, and add and the immiscible solvent of water (such as benzene, ether, ethyl acetate etc.) again, extract the purpose compound, the organic layer that extracts washes with water, with dryings such as anhydrous magnesium sulfates, then steam solvent, obtain the purpose compound.If necessary, can according to a conventional method, such as passing through the methods such as recrystallization, redeposition or chromatogram resulting purpose compound further be made with extra care.
In mixed anhydride method, make compound (XXVb) in inert solvent, in the presence of alkali, with mixed acid anhydride forming agent reaction, generate mixed acid anhydride, then make its in inert solvent with Ammonia, C 1-C 6Alkylamine or two (C 1-C 6Alkyl) amine reaction.
Employed solvent is not particularly limited in the reaction of making mixed acid anhydride, so long as do not hinder reaction and can initial substance dissolving person all can be used.The example of such solvent is the halogenated hydrocarbons such as methylene dichloride, aminoform, tetracol phenixin, ethylene dichloride, chlorobenzene or dichlorobenzene; The ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF), diox, glycol dimethyl ether or diglyme; Perhaps amidess such as methane amide, DMF, N,N-dimethylacetamide or hexamethyl phosphoric triamide, preferred ethers (especially tetrahydrofuran (THF)).
The mixed acid anhydride forming agent can be the C such as the haloformic acid such as Vinyl chloroformate or isobutyl chlorocarbonate 1-C 4Alkyl ester; The C such as pivalyl chloride 1-C 5Deng cyano group phosphoric acid C such as alkane carboxylic acid halides or diethyl phosphorocyanidate or cyano group diphenyl phosphates 1-C 4Alkyl ester or C 6-C 14Aryl ester, preferred haloformic acid C 1-C 4Alkyl ester (especially Vinyl chloroformate).
Employed alkali can be alkaline carbonate classes such as yellow soda ash, salt of wormwood or Quilonum Retard; Perhaps triethylamine, Tributylamine, diisopropyl ethyl amine, N-methylmorpholine, pyridine, 4-(N, the N-dimethylamino) pyridine, N, accelerine, N, N-Diethyl Aniline, 1,5-diazabicyclo [4.3.0] ninth of the ten Heavenly Stems-5-alkene, 1,4-diazabicyclo [2.2.2] octane (DABCO) or 1,8-diazabicyclo (5.4.0] 11 carbon-organic bases such as 7-alkene (DBU), preferred organic amine (especially triethylamine).
Temperature of reaction in making mixed anhydride reaction changes with starting compound and reagent etc., but normally ,-50 ℃-100 ℃ (preferred-10 ℃-50 ℃).
Reaction times in making mixed anhydride reaction changes with starting compound, reagent and temperature of reaction, but normally 5 minutes-20 hours (preferred 10 minutes-10 hours).
Employed solvent is not particularly limited in the reaction of mixed acid anhydride and Ammonia etc., so long as do not hinder reaction and can initial substance dissolving person all can be used.The example of such solvent is the ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF), diox, glycol dimethyl ether or diglyme; Or the amidess such as methane amide, DMF, N,N-dimethylacetamide or hexamethyl phosphoric triamide, preferred ethers (especially tetrahydrofuran (THF)).
The temperature of reaction of the reaction such as mixed acid anhydride and Ammonia changes with starting compound and reagent etc., but normally ,-30 ℃-100 ℃ (preferred 0 ℃-80 ℃).
The reaction times of the reaction such as mixed acid anhydride and Ammonia changes with starting compound, reagent and temperature of reaction, but normally 5 minutes-24 hours (preferred 10 minutes-5 hours).
React complete after, from reaction mixture, isolate according to a conventional method the purpose compound of this reaction.For example, react complete after, by steaming solvent, or in the residue that steams behind the solvent, add water, and add and the immiscible solvent of water (such as benzene, ether, ethyl acetate etc.) again, extract the purpose compound, the organic layer that extracts washes with water, with dryings such as anhydrous magnesium sulfates, then steam solvent, obtain the purpose compound.If necessary, can according to a conventional method, such as passing through the methods such as recrystallization, redeposition or chromatogram resulting purpose compound further be made with extra care.
In condensation method, make compound (XXVb) in inert solvent, in the presence of condensing agent, directly and Ammonia, C 1-C 6Alkylamine or two (C 1-C 6Alkyl) amine reaction.
Employed condensing agent can be dicyclohexyl carbodiimide, carbonyl dimidazoles or 1-methyl-2-chloro-iodate pyridine-triethylamine for example, preferred dicyclohexyl carbodiimide.
This reaction can with the reacting phase of aforementioned manufacturing Acibenzolar with condition under carry out.
React complete after, from reaction mixture, isolate according to a conventional method the purpose compound of this reaction.For example, react complete after, by steaming solvent, or in the residue that steams behind the solvent, add water, and add and the immiscible solvent of water (such as benzene, ether, ethyl acetate etc.) again, extract the purpose compound, the organic layer that extracts washes with water, with dryings such as anhydrous magnesium sulfates, then steam solvent, obtain the purpose compound.If necessary, can according to a conventional method, such as passing through the methods such as recrystallization, redeposition or chromatogram resulting purpose compound further be made with extra care.
Method L is general formula (XXVIb) or (XXVIc) manufacture method of compound.
Step L 1 is the step of making compound (XXVIb), this step is according to known method in the general Synthetic Organic Chemistry technology, by making general formula (XXVIa) compound in inert solvent or not existing under the condition of solvent, in the presence of acid or alkali, be hydrolyzed to finish.This reaction can be carried out under the condition identical with the reaction (d) of steps A 2.
Step L2 is the step of making compound (XXVIc), this step can be undertaken by known method in the Synthetic Organic Chemistry technology, the method of commonly using in for example synthesizing according to peptide (for example trinitride method, active ester method, mixed anhydride method or condensation method (preferred mixed anhydride method)), by making compound (XXVIb) in inert solvent, with Ammonia, C 1-C 6Alkylamine or two (C 1-C 6Alkyl) amine reacts to finish.This reaction can be carried out under the condition identical with the K3 step.
Method M is the manufacture method of general formula (XVI) compound or general formula (XXIII) compound.
Step M1 is the step of making compound (XVI) or compound (XXIII), and this step can be finished through the following steps, makes general formula (XXIII) compound or general formula (XXIX) compound
(1) in inert solvent, in the existence of alkali or not (preferably in the presence of alkali), with general formula R 12-Za or R 12A-O-R 12The reaction of compound shown in a, R in the formula 12, R 12The implication of a and Za as hereinbefore, or
(2) in inert solvent, in the presence of condensing agent and in the existence of alkali or not (preferably in the presence of alkali), with general formula R 12Compound reaction shown in the a-OH, R in the formula 12The implication of a as hereinbefore, or
(3) in inert solvent, in the presence of the halophosphoric acid dialkyl esters such as phosphorus chloride diethyl phthalate and alkali, with general formula R 12Compound reaction shown in the a-OH, R in the formula 12The implication of a as hereinbefore, perhaps
(4) in inert solvent, in the existence of acid or not (preferably in the presence of acid), with dihydrofuran or dihydropyrans reaction.Reaction can be carried out under the condition identical with step J1.
Method N is other approach manufacture method of general formula (III) compound.
Step N1 is the step of making general formula (XXXI) compound, and this step is by making general formula (XXX) compound in inert solvent or do not exist under the condition of solvent, being hydrolyzed to finish in the presence of acid or alkali.This reaction can be carried out under the condition identical with the reaction (d) of steps A 2.
Step N2 is the step of making general formula (XXXII) compound, and this step is by making compound (XXXI) in inert solvent, reacting to finish with general formula (XVI) compound in the presence of alkali.
Employed solvent is not particularly limited, so long as do not hinder reaction and can initial substance dissolving person all can be used.The example of such solvent is the aliphatic hydrocarbon such as hexane, hexanaphthene, heptane, solvent naphtha or sherwood oil; The aromatic hydrocarbons such as benzene, toluene or dimethylbenzene; Methylene dichloride, chloroform, tetracol phenixin, 1, the halohydrocarbon such as 2-ethylene dichloride, chlorobenzene or dichlorobenzene; The ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF), diox, glycol dimethyl ether or diglyme; The amidess such as methane amide, DMF, N,N-dimethylacetamide or METHYLPYRROLIDONE; The sulfoxide type such as dimethyl sulfoxide (DMSO) or tetramethylene sulfone; Preferred ethers (especially diethyl ether or tetrahydrofuran (THF)).
Employed alkali can be alkaline carbonate classes such as yellow soda ash, salt of wormwood or Quilonum Retard; The alkali metal hydrocarbonate classes such as sodium bicarbonate, saleratus or lithium bicarbonate; The alkalimetal hydride classes such as lithium hydride, sodium hydride or potassium hydride KH; The alkali metal hydroxides such as sodium hydroxide, potassium hydroxide or lithium hydroxide; The alkali metal alcohol salts such as sodium methylate, sodium ethylate, potassium tert.-butoxide or lithium methoxide; Triethylamine, Tributylamine, diisopropyl ethyl amine, N-methylmorpholine, pyridine, 4-(N, the N-dimethylamino) pyridine, N, accelerine, N, N-Diethyl Aniline, 1,5-diazabicyclo [4.3.0] ninth of the ten Heavenly Stems-5-alkene, 1,4-diazabicyclo [2.2.2] octane (DABCO) or 1,8-diazabicyclo [5.4.0], 11 carbon-organic bases such as 7-alkene (DBU); The lithium alkylide classes such as lithium methide, lithium ethide or butyllithium; The alkylamino lithiums such as diisopropylaminoethyl lithium or dicyclohexyl lithium amide; Perhaps basic metal hexamethyl two silicon trinitride such as hexamethyl two silicon potassium azide or hexamethyl two silicon sodiumazide, preferred alkyl lithium class (especially butyllithium) or alkylamino lithium class (especially diisopropylaminoethyl lithium).
Temperature of reaction changes with starting compound and reagent etc., but normally-150 ℃-50 ℃, preferred-100 ℃-0 ℃.
Reaction times changes with starting compound, reagent and temperature of reaction, but normally 10 minutes-10 hours, preferred 30 minutes-5 hours.
React complete after, from reaction mixture, isolate according to a conventional method the purpose compound of this step.For example, react complete after, in reaction mixture, add water, extract the purpose compound, then use acid (such as hydrochloric acid etc.) with the pH regulator of the water layer that extracts to acid, add and the immiscible solvent of water (such as benzene, ether, ethyl acetate etc.) again, extract the purpose compound, the organic layer that extracts washes with water, with dryings such as anhydrous magnesium sulfates, then steam solvent, obtain the purpose compound.If necessary, can according to a conventional method, such as passing through the methods such as recrystallization, redeposition or chromatogram resulting purpose compound further be made with extra care.
Step N3 is the step of making compound (III), and this step can be finished by following 2 steps:
(1) make compound (XXXII) in inert solvent, in the presence of alkali with halo carbonic acid (C 1-C 6Alkyl) ester reaction, then
(2) make resulting midbody compound in inert solvent, react with sodium borohydride.
Employed solvent is not particularly limited among the step N3 (1), so long as do not hinder reaction and can initial substance dissolving person all can be used.The example of such solvent is the aliphatic hydrocarbon such as hexane, hexanaphthene, heptane, solvent naphtha or sherwood oil; The aromatic hydrocarbons such as benzene, toluene or dimethylbenzene; Methylene dichloride, chloroform, tetracol phenixin, 1, the halohydrocarbon such as 2-ethylene dichloride, chlorobenzene or dichlorobenzene; The ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF), diox, glycol dimethyl ether or diglyme, preferred halogenated hydrocarbon (especially methylene dichloride) or ethers (especially diethyl ether or tetrahydrofuran (THF)).
Employed alkali can be alkaline carbonate classes such as yellow soda ash, salt of wormwood or Quilonum Retard among the step N3 (1); The alkali metal hydrocarbonate classes such as sodium bicarbonate, saleratus or lithium bicarbonate; The alkali metal hydroxides such as sodium hydroxide, potassium hydroxide or lithium hydroxide; Methylamine, dimethylamine, ethamine, triethylamine, Tributylamine, diisopropyl ethyl amine, N-methylmorpholine, pyridine, 4-(N, the N-dimethylamino) pyridine, N, accelerine, N, N-Diethyl Aniline, 1, the 5-diazabicyclo (4.3.0] ninth of the ten Heavenly Stems-5-alkene, 1,4-diazabicyclo [2.2.2] octane (DABCO) or 1,8-diazabicyclo [5.4.0], 11 carbon-organic bases such as 7-alkene (DBU), preferred organic bases (especially triethylamine).
" halo carbonic acid (C employed among the step N3 (1) 1-C 6Alkyl) ester " can be for example fluorine methyl carbonate, methyl-chlorocarbonate, bromine methyl carbonate, iodine methyl carbonate, fluorine ethyl-carbonate, chlorine ethyl-carbonate, ETHYL-4-BROMO CROTONATE, iodine ethyl-carbonate, fluorine propyl carbonate, chlorine butyl carbonate, bromine amyl carbonate or the own ester of iodine carbonic acid, preferred methyl-chlorocarbonate or chlorine ethyl-carbonate.
Temperature of reaction changes with starting compound and reagent etc., but normally-10 ℃-150 ℃, preferred 0 ℃-100 ℃.
Reaction times changes with starting compound, reagent and temperature of reaction, but normally 5 minutes-12 hours, preferred 10 minutes-6 hours.
React complete after, from reaction mixture, isolate according to a conventional method the purpose compound of this step.For example, react complete after, as required, remove by filter insolubles, then steam solvent, perhaps, react complete after, in reaction mixture, add entry, add and the immiscible solvent of water (such as benzene, ether, ethyl acetate etc.) again, extract the purpose compound, the organic layer that extracts washes with water, with dryings such as anhydrous magnesium sulfates, then steam solvent, obtain the purpose compound.If necessary, can according to a conventional method, such as passing through the methods such as recrystallization, redeposition or chromatogram resulting purpose compound further be made with extra care.
Employed solvent is not particularly limited among the step N3 (2), so long as do not hinder reaction and can initial substance dissolving person all can be used.The example of such solvent is the aliphatic hydrocarbon such as hexane, hexanaphthene, heptane, solvent naphtha or sherwood oil; The aromatic hydrocarbons such as benzene, toluene or dimethylbenzene; Methylene dichloride, chloroform, tetracol phenixin, 1, the halohydrocarbon such as 2-ethylene dichloride, chlorobenzene or dichlorobenzene; The ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF), diox, glycol dimethyl ether or diglyme, preferred ethers (especially diethyl ether or tetrahydrofuran (THF)).
Temperature of reaction changes with starting compound and reagent etc., but normally-10 ℃-150 ℃, preferred 0 ℃-100 ℃.
Reaction times changes with starting compound, reagent and temperature of reaction, but normally 1-48 hour, preferred 6-24 hour.
React complete after, from reaction mixture, isolate according to a conventional method the purpose compound of this step.For example, react complete after, in reaction mixture, add entry, add and the immiscible solvent of water (such as benzene, ether, ethyl acetate etc.), extract the purpose compound, the organic layer that extracts washes with water, with dryings such as anhydrous magnesium sulfates, then steam solvent, obtain the purpose compound.If necessary, can according to a conventional method, such as passing through the methods such as recrystallization, redeposition or chromatogram resulting purpose compound further be made with extra care.
Method O is the manufacture method as the general formula of the starting compound of method M (XXVIII) compound.
Step O1 is the step of making compound (XXVIII), this step be by general formula (XXXIII) compound in trifluoroacetic acid, finish with hexa-methylene four inferior reactions.
Temperature of reaction changes with starting compound and reagent etc., but normally, with the reaction of vulkacit H in, temperature of reaction is 0 ℃-150 ℃, preferred 50 ℃-120 ℃, with the reaction of sulfuric acid in, temperature of reaction is-20 ℃-100 ℃, preferred 0 ℃-50 ℃.
Reaction times changes with starting compound, reagent and temperature of reaction, but normally, with the reaction of vulkacit H in, the reaction times is 1-24 hour, preferred 6-12 hour.
React complete after, from reaction mixture, isolate according to a conventional method the purpose compound of this step.For example, react complete after, by steaming solvent; Perhaps, react complete after, steam solvent, in resulting residue, add water, add and the immiscible solvent of water (such as benzene, ether, ethyl acetate etc.) again, extract the purpose compound, the organic layer that extracts washes with water, with dryings such as anhydrous magnesium sulfates, then steam solvent, obtain the purpose compound.If necessary, can according to a conventional method, such as passing through the methods such as recrystallization, redeposition or chromatogram resulting purpose compound further be made with extra care.
Starting compound of the present invention (VII), (VIII), (IX), (X), (XV), (XVI), (XVII), (XVIII), (XIX), (XXII), (XXIII), (XXV), (XXVIII), (XXIX), (XXX) and be known (XXXIII) etc. maybe can (for example easily be made by known method Bioorg.Med. Chem Lett., 8, 277 (1998), Tetrahedron Letters, 37, 6439 (1996) etc.).
Implement best mode of the present invention
The following example and formulation example are used for further specifying the present invention, but scope of the present invention is not limited to these examples.
In addition, nucleus magnetic resonance (NMR) wave spectrum is to represent with respect to the δ value (ppm) as interior target tetramethylsilane.Binding constant J value represents with Hz, and is approximate to 0.5Hz.Use following abbreviation in the data:
D: bimodal
Dd: two-fold is bimodal
Ddd: two two-folds are bimodal
Dt: double three peaks
T: triplet
Q: quartet
M: multiplet
S: unimodal
Bs: wide unimodal
Embodiment 1
N-(4-(1-acetimidoyl piperidin-4-yl oxygen) phenyl)-N-(3-(3-carbamimido-phenyl)-2-(E)-propenyl) ethyl sulfonamide dihydrochloride (exemplary compounds number: 1080)
(a) N-(3-(3-carbamimido-phenyl)-2-(E)-propenyl)-N-(4-(piperidin-4-yl oxygen) phenyl) ethyl sulfonamide dihydrochloride
N-(4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen) phenyl)-N-(3-(3-cyano-phenyl)-2-(E)-propenyl) ethyl sulfonamide (955mg) is dissolved in the mixed solvent of methylene dichloride (40ml) and ethanol (20ml), passed into hydrogenchloride 1 hour under ice-cooled, the gained mixture at room temperature stirred in the reactor of jam-pack 9 hours.With the reaction mixture concentrating under reduced pressure, the gained residue is dissolved in the ethanol (30ml), adds aqueous ammonium chloride solution (193mg is dissolved in the 10ml water) and 28% ammoniacal liquor (0.375ml), then at room temperature places 12 hours.Under reduced pressure steam solvent, residue is dissolved in the methyl alcohol (20ml), adds 4M hydrogenchloride dioxane solution (2ml), then concentrating under reduced pressure.Residue preparative HPLC (YMC-Pack ODS YMC, elutriant: 15% acetonitrile solution) refining, the amorphous solid that obtains is dissolved in the methyl alcohol (10ml), adds 4M hydrogenchloride dioxane solution (1ml), then under reduced pressure is concentrated into dried.In the gained amorphous solid water-soluble (approximately 10ml), after lyophilize, obtain colourless amorphous solid title compound 354mg (yield 44%).
1H?NMR(500MHz，DMSO-d 6)δppm：1.27(3H，t，J＝7.0)，1.83(2H，m)，2.09(2H，m)，3.03(2H，m)，3.17(2H，q，J＝7.0)，3.19(2H，m)，4.45(2H，d，J＝6.0)，4.64(1H，m)，6.45(1H，dt，J＝16.0，6.0)，6.55(1H，d，J＝16.0)，7.00(2H，d，J＝9.0)，7.37(2H，d，J＝9.0)，7.54(1H，t，J＝8.0)，7.70(2H，m)，7.89(1H，s)；
MS(FAB)m/z＝443(M+H) +。
(b) N-(4-(1-acetimidoyl piperidin-4-yl oxygen) phenyl)-N-(3-(3-carbamimido-phenyl)-2-(E)-propenyl) ethyl sulfonamide dihydrochloride
N-(3-(3-carbamimido-phenyl)-2-(E)-propenyl)-N-(4-(piperidin-4-yl oxygen) phenyl) ethyl sulfonamide dihydrochloride (311mg) is dissolved in the ethanol (10ml), add second imido acid ethyl ester (ethyl acetimidate) hydrochloride (260mg) and triethylamine (0.500ml), then at room temperature stirred 12 hours.In reaction mixture, add 4M hydrogenchloride dioxane solution (1ml), then concentrating under reduced pressure.(YMC-Pack ODS YMC, elutriant: 20% acetonitrile solution) refining, the gained amorphous solid is dissolved in the methyl alcohol (10ml) residue, adds 4M hydrogenchloride dioxane solution (0.5ml), then is evaporated to dried with preparative HPLC.In the gained amorphous solid water-soluble (approximately 10ml), after lyophilize, obtain colourless amorphous solid title compound 243mg (yield 62%).
1H?NMR(500MHz，DMSO-d 6)δppm：1.27(3H，t，J＝7.0)，1.72(2H，m)，2.04(2H，m)，2.30(3H，s)，3.18(2H，q，J＝7.0)，3.50-3.59(2H，m)，3.72(1H，m)，3.84(1H，m)，4.45(2H，d，J＝6.0)，4.70(1H，m)，6.46(1H，dt，J＝15.5，6.0)，6.55(1H，d，J＝15.5)，7.01(2H，d，J＝9.0)，7.37(2H，d，J＝9.0)，7.54(1H，t，J＝8.0)，7.71(2H，m)，7.91(1H，s)；
IR(KBr，cm -1)：1674，1625。
Embodiment 2
N-(4-(1-acetimidoyl piperidin-4-yl oxygen) phenyl)-N-(3-(3-carbamimido-phenyl)-2-methyl-2-(E)-propenyl) ethyl sulfonamide dihydrochloride (exemplary compounds number: 1220)
(a) N-(3-(3-carbamimido-phenyl)-2-methyl-2-(E)-propenyl)-N-(4-(piperidin-4-yl oxygen) phenyl) ethyl sulfonamide dihydrochloride
N-(4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen) phenyl)-N-(3-(3-cyano-phenyl)-2-methyl-2-(E)-propenyl) ethyl sulfonamide (955mg) is dissolved in the mixed solvent of methylene dichloride (40ml) and ethanol (20ml), passed into hydrogenchloride 1 hour under ice-cooled, the gained mixture at room temperature stirred in the reactor of jam-pack 8 hours.With the reaction mixture concentrating under reduced pressure, the gained residue is dissolved in the ethanol (30ml), adds aqueous ammonium chloride solution (166mg is dissolved in the 10ml water) and 28% ammoniacal liquor (0.320ml), then at room temperature places 12 hours.Under reduced pressure steam solvent, residue is dissolved in the methyl alcohol (20ml), adds 4M hydrogenchloride dioxane solution (1ml), then concentrating under reduced pressure.Residue preparative HPLC (YMC-Pack ODS YMC, elutriant: 15% acetonitrile solution) refining, the amorphous solid that obtains is dissolved in the methyl alcohol (20ml), adds 4M hydrogenchloride dioxane solution (1ml), then under reduced pressure is concentrated into dried.In the gained amorphous solid water-soluble (approximately 70ml), after lyophilize, obtain colourless amorphous solid title compound 514mg (yield 63%).
1H?NMR(500MHz，DMSO-d 6)δppm：1.27(3H，t，J＝7.0)，1.84(2H，m)，1.87(3H，s)，2.09(2H，m)，3.04(2H，m)，3.16(2H，q，J＝7.0)，3.20(2H，m)，4.39(2H，s)，4.64(1H，m)，6.35(1H，s)，7.01(2H，d，J＝9.5)，7.39(2H，d，J＝9.5)，7.47(1H，d，J＝8.0)，7.55(2H，m)，7.64(1H，d，J＝8.0)；
IR(KBr，cm -1)：1675。
(b) N-(4-(1-acetimidoyl piperidin-4-yl oxygen) phenyl)-N-(3-(3-carbamimido-phenyl)-2-methyl-2-(E)-propenyl) ethyl sulfonamide dihydrochloride
N-(3-(3-carbamimido-phenyl)-2-methyl-2-(E)-propenyl)-N-(4-(piperidin-4-yl oxygen) phenyl) ethyl sulfonamide dihydrochloride (303mg) is dissolved in the ethanol (10ml), add iminoester hydrochloride (246mg) and triethylamine (0.460ml), then at room temperature stirred 12 hours.In reaction mixture, add 4M hydrogenchloride dioxane solution (0.9ml), then concentrating under reduced pressure.(YMC-Pack ODSYMC, elutriant: 20% acetonitrile solution) refining, the gained amorphous solid is dissolved in the methyl alcohol (10ml) residue, adds 4M hydrogenchloride dioxane solution (0.4ml), then is evaporated to dried with preparative HPLC.In the gained amorphous solid water-soluble (approximately 10ml), after lyophilize, obtain colourless amorphous solid title compound 170mg (yield 45%).
1H?NMR(500MHz，DMSO-d 6)δppm：1.27(3H，t，J＝7.0)，1.71(2H，m)，1.87(3H，s)，2.04(2H，m)，2.30(3H，s)，3.17(2H，q，J＝7.0)，3.53(2H，m)，3.72(1H，m)，3.83(1H，m)，4.39(2H，s)，4.70(1H，m)，6.35(1H，s)，7.01(2H，d，J＝9.0)，7.39(2H，d，J＝9.0)，7.47(1H，d，J＝8.0)，7.55(1H，s)，7.55(1H，t，J＝8.0)，7.65(1H，d，J＝8.0)；
IR(KBr，cm -1)：1673，1626。
Embodiment 3
N-(4-(1-acetimidoyl piperidin-4-yl oxygen) phenyl)-N-(3-(3-carbamimido-phenyl)-2-(E)-propenyl) sulphonamide ethyl acetate dihydrochloride (exemplary compounds number: 1410)
(a) N-(3-(3-carbamimido-phenyl)-2-(E)-propenyl)-N-(4-(piperidin-4-yl oxygen) phenyl) sulphonamide ethyl acetate dihydrochloride
N-(4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen) phenyl)-N-(3-(3-cyano-phenyl)-2-(E)-propenyl) sulphonamide ethyl acetate (1.46g) is dissolved in the mixed solvent of methylene dichloride (50ml) and ethanol (25ml), passed into hydrogenchloride 1 hour under ice-cooled, the gained mixture at room temperature stirred in the reactor of jam-pack 8 hours.With the reaction mixture concentrating under reduced pressure, the gained residue is dissolved in the ethanol (40ml), adds aqueous ammonium chloride solution (0.3g is dissolved in the 15ml water) and 28% ammoniacal liquor (0.58ml), then at room temperature places 12 hours.In reaction mixture, add 4M hydrogenchloride dioxane solution (2ml), then concentrating under reduced pressure.The residue preparative HPLC (YMC-Pack ODS YMC, elutriant: 15% acetonitrile solution) refining, obtain faint yellow amorphous solid title compound 0.98g (yield 68%).
1H?NMR(500MHz，DMSO-d 6)δppm：1.23(3H，t，J＝7.0)，1.83(2H，m)，2.10(2H，m)，3.05(2H，m)，3.19(2H，m)，4.20(2H，q，J＝7.0)，4.34(2H，s)，4.45(2H，d，J＝6.0)，4.66(1H，m)，6.45(1H，dt，J＝16.0，6.0)，6.55(1H，d，J＝16.0)，7.04(2H，d，J＝8.5)，7.39(2H，d，J＝8.5)，7.55(1H，t，J＝8.0)，7.69(1H，d，J＝8.0)，7.72(1H，d，J＝8.0)，7.89(1H，s)；
IR(KBr，cm -1)：1737，1675。
(b) N-(4-(1-acetimidoyl piperidin-4-yl oxygen) phenyl)-N-(3-(3-carbamimido-phenyl)-2-(E)-propenyl) sulphonamide ethyl acetate dihydrochloride
N-(3-(3-carbamimido-phenyl)-2-(E)-propenyl)-N-(4-(piperidin-4-yl oxygen) phenyl) sulphonamide ethyl acetate dihydrochloride (1090mg) is dissolved in the ethanol (40ml), add iminoester hydrochloride (705mg) and triethylamine (1.30ml), then at room temperature stirred 6 hours.Reaction mixture under reduced pressure is concentrated into dried, and residue is dissolved in the methyl alcohol (15ml), adds 4M hydrogenchloride dioxane solution (2ml), then concentrating under reduced pressure.(YMC-Pack ODS YMC, elutriant: 20% acetonitrile solution) refining, the gained amorphous solid is dissolved in the methyl alcohol (15ml) residue, adds 4M hydrogenchloride dioxane solution (1ml), then is evaporated to dried with preparative HPLC.Obtain colourless amorphous solid title compound 812mg (yield 70%).
1H?NMR(500MHz，DMSO-d 6)δppm：1.23(3H，t，J＝7.0)，1.67-1.79(2H，m)，2.04(2H，m)，2.29(3H，s)，3.50(2H，m)，3.72(1H，m)，3.81(1H，m)，4.19(2H，q，J＝7.0)，4.34(2H，s)，4.44(2H，d，J＝6.0)，4.70(1H，m)，6.45(1H，dt，J＝16.5，6.0)，6.55(1H，d，J＝16.5)，7.04(2H，d，J＝9.5)，7.39(2H，d，J＝9.5)，7.54(1H，t，J＝8.0)，7.69(1H，d，J＝8.0)，7.71(1H，d，J＝8.0)，7.88(1H，s)；
IR(KBr，cm -1)：1738，1673，1626。
Embodiment 4
N-(4-(1-acetimidoyl piperidin-4-yl oxygen) phenyl)-N-(3-(3-carbamimido-phenyl)-2-(E)-propenyl) sulphonamide acetic acid dihydrochloride (exemplary compounds number: 1939)
N-(4-(1-acetimidoyl piperidin-4-yl oxygen) phenyl)-N-(3-(3-carbamimido-phenyl)-2-(E)-propenyl) sulphonamide ethyl acetate dihydrochloride (440mg) is dissolved in the 3M hydrochloric acid (30ml), stirs 3 hours at 80 ℃.Reaction mixture carries out concentrating under reduced pressure after being cooled to room temperature, residue preparative HPLC (YMC-Pack ODS YMC, elutriant: 15% acetonitrile solution) refining, the gained amorphous solid is dissolved in the methyl alcohol (15ml), add 4M hydrogenchloride dioxane solution (1ml), then under reduced pressure be concentrated into dried.Residue is dissolved in the water (approximately 15ml), obtains title compound 331mg (yield 78%) after lyophilize.
1H?NMR(500MHz，DMSO-d 6)δppm：1.73(2H，m)，2.04(2H，m)，2.29(3H，s)，3.51(2H，m)，3.72(1H，m)，3.80(1H，m)，4.18(2H，s)，4.45(2H，d，J＝6.0)，4.70(1H，m)，6.44(1H，dt，J＝16.5，6.0)，6.55(1H，d，J＝16.5)，7.03(2H，d，J＝8.5)，7.40(2H，d，J＝8.5)，7.54(1H，t，J＝8.0)，7.68(1H，d，J＝8.0)，7.71(1H，d，J＝8.0)，7.87(1H，s)；
IR(KBr，cm -1)：1733，1673，1627。
Embodiment 5
N-(4-(1-acetimidoyl piperidin-4-yl oxygen) phenyl)-N-(3-(5-amidino groups-2-fluorophenyl)-2-(E)-propenyl) ethyl sulfonamide dihydrochloride (exemplary compounds number: 1280)
(a) N-(3-(5-amidino groups-2-fluorophenyl)-2-(E)-propenyl)-N-(4-(piperidin-4-yl oxygen) phenyl) ethyl sulfonamide dihydrochloride
N-(4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen) phenyl)-N-(3-(5-cyano group-2-fluorophenyl)-2-(E)-propenyl) ethyl sulfonamide (2.00g) is dissolved in the mixed solvent of methylene dichloride (60ml) and ethanol (40ml), passed into hydrogenchloride 1 hour under ice-cooled, the gained mixture at room temperature stirred in the reactor of jam-pack 7 hours.With the reaction mixture concentrating under reduced pressure, the gained residue is dissolved in the ethanol (50ml), adds aqueous ammonium chloride solution (0.39g is dissolved in the 25ml water) and 28% ammoniacal liquor (0.76ml), then at room temperature places 12 hours.With the reaction mixture concentrating under reduced pressure, residue is dissolved in the methyl alcohol (20ml), adds 4M hydrogenchloride dioxane solution (2ml), then concentrating under reduced pressure.Residue preparative HPLC (YMC-Pack ODS YMC, elutriant: 20% acetonitrile solution) refining, the amorphous solid that obtains is dissolved in the methyl alcohol (10ml), adds 4M hydrogenchloride dioxane solution (1ml), then under reduced pressure is concentrated into dried.In the gained amorphous solid water-soluble (approximately 70ml), after lyophilize, obtain light brown amorphous solid title compound 1.20g (yield 61%).
1H?NMR(500MHz，DMSO-d 6)δppm：1.27(3H，t，J＝7.0)，1.82(2H，m)，2.09(2H，m)，3.04(2H，m)，3.17(2H，q，J＝7.0)，3.18(2H，m)，4.49(2H，d，J＝6.0)，4.64(1H，m)，6.55(1H，dt，J＝16.0，6.0)，6.61(1H，d，J＝16.0)，7.01(2H，d，J＝8.5)，7.37(2H，d，J＝8.5)，7.45(1H，m)，7.78(1H，m)，8.11(1H，m)；
IR(KBr，cm -1)：3056，1?676。
(b) N-(4-(1-acetimidoyl piperidin-4-yl oxygen) phenyl)-N-(3-(5-amidino groups-2-fluorophenyl)-2-(E)-propenyl) ethyl sulfonamide dihydrochloride
N-(3-(5-amidino groups-2-fluorophenyl)-2-(E)-propenyl)-N-(4-(piperidin-4-yl oxygen) phenyl) ethyl sulfonamide dihydrochloride (534mg) is dissolved in the ethanol (20ml), at room temperature add iminoester hydrochloride (371mg) and triethylamine (0.70ml), then under same temperature, stirred 12 hours.In reaction mixture, add 4M hydrogenchloride dioxane solution (2ml), then concentrating under reduced pressure.(YMC-Pack ODSYMC, elutriant: 20% acetonitrile solution) refining, the gained amorphous solid is dissolved in the methyl alcohol (10ml) residue, adds 4M hydrogenchloride dioxane solution (0.5ml), then is evaporated to dried with preparative HPLC.In the gained amorphous solid water-soluble (approximately 10ml), after lyophilize, obtain colourless amorphous solid title compound 415mg (yield 75%).
1H?NMR(500MHz，DMSO-d 6)δppm：1.28(3H，t，J＝7.0)，1.74(2H，m)，2.05(2H，m)，2.30(3H，s)，3.18(2H，q，J＝7.0)，3.52(2H，m)，3.72(1H，m)，3.81(1H，m)，4.50(2H，d，J＝6.0)，4.70(1H，m)，6.56(1H，dt，J＝16.5，6.0)，6.62(1H，d，J＝16.5)，7.02(2H，d，J＝9.0)，7.37(2H，d，J＝9.0)，7.46(1H，m)，7.78(1H，m)，8.12(1H，m)；
IR(KBr，cm -1)：3113，1674，1625。
Embodiment 6
N-(4-(1-acetimidoyl piperidin-4-yl oxygen)-2-aminomethyl phenyl)-N-(3-(3-carbamimido-phenyl)-2-(E)-propenyl) sulphonamide ethyl acetate dihydrochloride (exemplary compounds number: 1419)
(a) N-(3-(3-carbamimido-phenyl)-2-(E)-propenyl)-N-(2-methyl-4-(piperidin-4-yl oxygen) phenyl) sulphonamide ethyl acetate dihydrochloride
N-(4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-2-aminomethyl phenyl)-N-(3-(3-cyano-phenyl)-2-(E)-propenyl) sulphonamide ethyl acetate (1.80g) is dissolved in the mixed solvent of methylene dichloride (60ml) and ethanol (40ml), passed into hydrogenchloride 1 hour under ice-cooled, the gained mixture at room temperature stirred in the reactor of jam-pack 6 hours.With the reaction mixture concentrating under reduced pressure, the gained residue is dissolved in the ethanol (50ml), adds aqueous ammonium chloride solution (0.32g is dissolved in the 25ml water) and 28% ammoniacal liquor (0.62ml), then at room temperature places 12 hours.With the reaction mixture concentrating under reduced pressure, residue is dissolved in the methyl alcohol (30ml), adds 4M hydrogenchloride dioxane solution (2ml), then concentrating under reduced pressure.The residue preparative HPLC (YMC-Pack ODS YMC, elutriant: 20% acetonitrile solution) refining, obtain colourless amorphous solid title compound 0.7g (yield 45%).
1H?NMR(500MHz，DMSO-d 6)δppm：1.23(3H，t，J＝7.0)，1.73(2H，m)，2.04(2H，m)，2.27(3H，s)，3.00(2H，m)，3.18(2H，m)，4.20(2H，q，J＝7.0)，4.25(1H，m)，4.33(1H，d，J＝14.5)，4.45(1H，m)，4.46(1H，d，J＝14.5)，4.59(1H，m)，6.46(2H，s)，6.88(1H，d，J＝9.0)，6.90(1H，s)，7.39(1H，d，J＝9.0)，7.55(1H，t，J＝8.0)，7.67(1H，d，J＝8.0)，7.71(1H，d，J＝8.0)，7.81(1H，s)；
IR(KBr，cm -1)：1737，1676。
(b) N-(4-(1-acetimidoyl piperidin-4-yl oxygen)-2-aminomethyl phenyl)-N-(3-(3-carbamimido-phenyl)-2-(E)-propenyl) sulphonamide ethyl acetate dihydrochloride
N-(3-(3-carbamimido-phenyl)-2-(E)-propenyl)-N-(2-methyl-4-(piperidin-4-yl oxygen) phenyl) sulphonamide ethyl acetate dihydrochloride (631mg) is dissolved in the ethanol (30ml), add iminoester hydrochloride (397mg) and triethylamine (0.75ml), then at room temperature stirred 64 hours.In reaction mixture, add 4M hydrogenchloride dioxane solution (2ml), then concentrating under reduced pressure.(YMC-Pack ODS YMC, elutriant: 24% acetonitrile solution) refining, the gained amorphous solid is dissolved in the methyl alcohol (20ml) residue, adds 4M hydrogenchloride dioxane solution (1ml), then is evaporated to dried with preparative HPLC.In the gained amorphous solid water-soluble (approximately 15ml), after lyophilize, obtain colourless amorphous solid title compound 423mg (yield 60%).
1H?NMR(500MHz，DMSO-d 6)δppm：1.24(3H，t，J＝6.5)，1.65-1.79(2H，m)，2.04(2H，m)，2.28(3H，s)，2.31(3H，s)，3.48-3.59(2H，m)，3.72(1H，m)，3.85(1H，m)，4.21(2H，q，J＝6.5)，4.28(1H，dd，J＝14.5，6.0)，4.34(1H，d，J＝15.0)，4.43(1H，dd，J＝14.5，4.5)，4.49(1H，d，J＝15.0)，4.70(1H，m)，6.46(1H，d，J＝15.5)，6.49(1H，m)，6.90(1H，dd，J＝9.0，3.0)，6.93(1H，d，J＝3.0)，7.41(1H，d，J＝9.0)，7.55(1H，t，J＝8.0)，7.72(2H，m)，7.88(1H，s)；
IR(KBr，cm -1)：1738，1673，1624。
Embodiment 7
N-(4-(1-acetimidoyl piperidin-4-yl oxygen)-3-p-methoxy-phenyl)-N-(3-(3-carbamimido-phenyl)-2-(E)-propenyl) sulphonamide ethyl acetate dihydrochloride (exemplary compounds number: 1442)
(a) N-(3-(3-carbamimido-phenyl)-2-(E)-propenyl)-N-(3-methoxyl group-4-(piperidin-4-yl oxygen) phenyl) sulphonamide ethyl acetate dihydrochloride
N-(4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-3-p-methoxy-phenyl)-N-(3-(3-cyano-phenyl)-2-(E)-propenyl) sulphonamide ethyl acetate (985mg) is dissolved in the mixed solvent of methylene dichloride (30ml) and ethanol (15ml), passed into hydrogenchloride 40 minutes under ice-cooled, the gained mixture at room temperature stirred in the reactor of jam-pack 6 hours.With the reaction mixture concentrating under reduced pressure, the gained residue is dissolved in the ethanol (20ml), adds aqueous ammonium chloride solution (172mg is dissolved in the 10ml water) and 28% ammoniacal liquor (0.33ml), then at room temperature places 13 hours.With the reaction mixture concentrating under reduced pressure, residue is dissolved in the methyl alcohol (20ml), adds 4M hydrogenchloride dioxane solution (1.5ml), then concentrating under reduced pressure.(YMC-Pack ODS YMC, elutriant: 17% acetonitrile solution) refining, the amorphous solid that obtains is dissolved in the mixture of methyl alcohol (20ml) and 4M hydrogenchloride dioxane solution (0.4ml) residue, then is concentrated into dried with preparative HPLC.Obtain faint yellow amorphous solid title compound 560mg (yield 58%).
1H?NMR(500MHz，DMSO-d 6)δppm：1.24(3H，t，J＝7.0)，1.84(2H，m)，2.05(2H，m)，3.03(2H，m)，3.19(2H，m)，3.79(3H，s)，4.21(2H，q，J＝7.0)，4.38(2H，s)，4.46(2H，d，J＝6.0)，4.56(1H，m)，6.46(1H，dt，J＝15.5，6.0)，6.57(1H，d，J＝15.5)，6.98(1H，dd，J＝9.0，2.0)，7.08(1H，d，J＝9.0)，7.11(1H，d，J＝2.0)，7.55(1H，t，J＝7.5)，7.69(1H，d，J＝7.5)，7.73(1H，d，J＝7.5)，7.90(1H，s)；
IR(KBr，cm -1)：1737，1675.
(b) N-(4-(1-acetimidoyl piperidin-4-yl oxygen)-3-p-methoxy-phenyl)-N-(3-(3-carbamimido-phenyl)-2-(E)-propenyl) sulphonamide ethyl acetate dihydrochloride
N-(3-(3-carbamimido-phenyl)-2-(E)-propenyl)-N-(3-methoxyl group-4-(piperidin-4-yl oxygen) phenyl) sulphonamide ethyl acetate dihydrochloride (392mg) is dissolved in the ethanol (20ml), add iminoester hydrochloride (241mg) and triethylamine (0.452ml), then at room temperature stirred 38 hours.In reaction mixture, add 4M hydrogenchloride dioxane solution (0.8ml), then concentrating under reduced pressure.(YMC-Pack ODS YMC, elutriant: 20% acetonitrile solution) refining, the gained amorphous solid is dissolved in the methyl alcohol (20ml) residue, adds 4M hydrogenchloride dioxane solution (0.3ml), then is evaporated to dried with preparative HPLC.In the gained amorphous solid water-soluble (approximately 10ml), after lyophilize, obtain colourless amorphous solid title compound 317mg (yield 76%).
1H?NMR(500MHz，DMSO-d 6)δppm：1.24(3H，t，J＝7.0)，1.66-1.80(2H，m)，2.01(2H，m)，2.30(3H，s)，3.47-3.59(2H，m)，3.72(1H，m)，3.78(3H，s)，3.82(1H，m)，4.21(2H，q，J＝7.0)，4.39(2H，s)，4.47(2H，d，J＝5.5)，4.62(1H，m)，6.47(1H，dt，J＝15.5，5.5)，6.57(1H，d，J＝15.5)，6.99(1H，dd，J＝9.0，3.0)，7.11(2H，m)，7.55(1H，t，J＝8.0)，7.71(1H，d，J＝8.0)，7.73(1H，d，J＝8.0)，7.91(1H，s)；
IR(KBr，cm -1)：1738，1674，1625.
Embodiment 8
N-(4-(1-acetimidoyl piperidin-4-yl oxygen)-3-chloro-phenyl-)-N-(3-(3-carbamimido-phenyl)-2-(E)-propenyl) sulphonamide ethyl acetate dihydrochloride (exemplary compounds number: 1414)
(a) N-(3-(3-carbamimido-phenyl)-2-(E)-propenyl)-N-(3-chloro-4-(piperidin-4-yl oxygen) phenyl) sulphonamide ethyl acetate dihydrochloride
N-(4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen) 3-chloro-phenyl-)-N-(3-(3-cyano-phenyl)-2-(E)-propenyl) sulphonamide ethyl acetate (1200mg) is dissolved in the mixed solvent of methylene dichloride (30ml) and ethanol (20ml), passed into hydrogenchloride 2 hours under ice-cooled, the gained mixture at room temperature stirred in the reactor of jam-pack 4 hours.With the reaction mixture concentrating under reduced pressure, the gained residue is dissolved in the ethanol (20ml), adds aqueous ammonium chloride solution (208mg is dissolved in the 10ml water) and 28% ammoniacal liquor (0.40ml), then at room temperature places 13 hours.With the reaction mixture concentrating under reduced pressure, residue is dissolved in the methyl alcohol (25ml), adds 4M hydrogenchloride dioxane solution (1.6ml), then concentrating under reduced pressure.(YMC-Pack ODS YMC, elutriant: 20% acetonitrile solution) refining, the amorphous solid that obtains is dissolved in the methyl alcohol (20ml) residue, adds 4M hydrogenchloride dioxane solution (0.5ml), then is concentrated into dried with preparative HPLC.The gained amorphous solid is soluble in water, obtains faint yellow amorphous solid title compound 662mg (yield 56%) after lyophilize.
1H?NMR(500MHz，DMSO-d 6)δppm：1.23(3H，t，J＝7.0)，1.88(2H，m)，2.10(2H，m)，3.08(2H，m)，3.17(2H，m)，4.19(2H，q，J＝7.0)，4.41(2H，s)，4.47(2H，d，J＝6.5)，4.78(1H，m)，6.44(1H，dt，J＝16.0，6.5)，6.57(1H，d，J＝16.0)，7.30(1H，d，J＝9.5)，7.41(1H，dd，J＝9.5，2.5)，7.55(1H，t，J＝8.0)，7.59(1H，d，J＝2.5)，7.69(1H，d，J＝8.0)，7.73(1H，d，J＝8.0)，7.88(1H，s)；
IR(KBr，cm -1)：1737，1675。
(b) N-(4-(1-acetimidoyl piperidin-4-yl oxygen)-3-chloro-phenyl-)-N-(3-(3-carbamimido-phenyl)-2-(E)-propenyl) sulphonamide ethyl acetate dihydrochloride
N-(3-(3-carbamimido-phenyl)-2-(E)-propenyl)-N-(3-chloro-4-(piperidin-4-yl oxygen) phenyl) sulphonamide ethyl acetate dihydrochloride (387mg) is dissolved in the ethanol (10ml), add iminoester hydrochloride (232mg) and triethylamine (0.440ml), then at room temperature stirred 5 hours.In reaction mixture, add 4M hydrogenchloride dioxane solution (1ml), then concentrating under reduced pressure.(YMC-Pack ODS YMC, elutriant: 22% acetonitrile solution) refining, the gained amorphous solid is dissolved in the methyl alcohol (20ml) residue, adds 4M hydrogenchloride dioxane solution (0.25ml), then is evaporated to dried with preparative HPLC.In the gained amorphous solid water-soluble (approximately 15ml), after lyophilize, obtain colourless amorphous solid title compound 268mg (yield 66%).
1H?NMR(500MHz，DMSO-d 6)δppm：1.23(3H，t，J＝7.0)，1.80(2H，m)，2.05(2H，m)，2.30(3H，s)，3.55-3.78(4H，m)，4.19(2H，q，J＝7.0)，4.42(2H，s)，4.47(2H，d，J＝6.0)，4.84(1H，m)，6.45(1H，dt，J＝15.5，6.0)，6.58(1H，d.J＝15.5)，7.33(1H，d，J＝9.0)，7.41(1H，dd，J＝9.0，3.0)，7.55(1H，t，J＝8.0)，7.59(1H，d，J＝3.0)，7.70(1H，d，J＝8.0)，7.73(1H，d，J＝8.0)，7.90(1H，s)；
IR(KBr，cm -1)：1738，1673，1623。
Embodiment 9
N-(4-(1-acetimidoyl piperidin-4-yl oxygen)-3-chloro-phenyl-)-N-(3-(3-carbamimido-phenyl)-2-(E)-propenyl) sulphonamide acetic acid dihydrochloride (exemplary compounds number: 1943)
N-(4-(1-acetimidoyl piperidin-4-yl oxygen)-3-chloro-phenyl-)-N-(3-(3-carbamimido-phenyl)-2-(E)-propenyl) sulphonamide ethyl acetate dihydrochloride (187mg) is dissolved in the 3M hydrochloric acid (7ml), stirs 2 hours at 80 ℃.Reaction mixture carries out concentrating under reduced pressure after being cooled to room temperature, residue preparative HPLC (YMC-PackODS YMC, elutriant: 15% acetonitrile solution) refining, the gained amorphous solid is dissolved in the methyl alcohol (10ml), add 4M hydrogenchloride dioxane solution (0.2ml), then under reduced pressure be concentrated into dried.Residue is dissolved in the water (approximately 10ml), obtains title compound 147mg (yield 82%) after lyophilize.
1H?NMR(500MHz，DMSO-d 6)δppm：1.79(2H，m)，2.05(2H，m)，2.29(3H，s)，3.54-3.75(4H，m)，4.23(2H，s)，4.47(2H，d，J＝6.0)，4.83(1H，m)，6.45(1H，dt，J＝16.0，6.0)，6.57(1H，d，J＝16.0)，7.32(1H，d，J＝9.0)，7.41(1H，m)，7.55(1H，t，J＝8.0)，7.60(1H，m)，7.68(1H，d，J＝8.0)，7.73(1H，d，J＝8.0)，7.88(1H，s)；
IR(KBr，cm -1)：1734，1673，1625。
Embodiment 10
N-(4-(1-acetimidoyl piperidin-4-yl oxygen)-3-fluorophenyl)-N-(3-(3-carbamimido-phenyl)-2-(E)-propenyl) sulphonamide ethyl acetate dihydrochloride (exemplary compounds number: 1412)
(a) N-(3-(3-carbamimido-phenyl)-2-(E)-propenyl)-N-(3-fluoro-4-(piperidin-4-yl oxygen) phenyl) sulphonamide ethyl acetate dihydrochloride
N-(4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen) phenyl)-N-(3-(3-cyano-phenyl)-2-(E)-propenyl) sulphonamide ethyl acetate (1210mg) is dissolved in the mixed solvent of methylene dichloride (30ml) and ethanol (20ml), passed into hydrogenchloride 1 hour under ice-cooled, the gained mixture at room temperature stirred in the reactor of jam-pack 6 hours.With the reaction mixture concentrating under reduced pressure, the gained residue is dissolved in the ethanol (20ml), adds aqueous ammonium chloride solution (215mg is dissolved in the 10ml water) and 28% ammoniacal liquor (0.41ml), then at room temperature places 17 hours.With the reaction mixture concentrating under reduced pressure, residue is dissolved in the methyl alcohol (20ml), adds 4M hydrogenchloride dioxane solution (2ml), then concentrating under reduced pressure.Residue preparative HPLC (YMC-Pack ODS YMC, elutriant: 17% acetonitrile solution) refining, the amorphous solid that obtains is dissolved in the methyl alcohol (15ml), adds 4M hydrogenchloride dioxane solution (0.3ml), then under reduced pressure is concentrated into dried.Obtain faint yellow amorphous solid title compound 798mg (yield 67%).
1H?NMR(500MHz，DMSO-d 6)δppm：1.23(3H，t，J＝7.0)，1.85(2H，m)，2.09(2H，m)，3.06(2H，m)，3.19(2H，m)，4.19(2H，q，J＝7.0)，4.40(2H，s)，4.47(2H，d，J＝7.0)，4.68(1H，m)，6.43(1H，m)，6.58(1H，d，J＝16.0)，7.25(1H，dd，J＝9.0，2.5)，7.3?1(1H，t，J＝9.0)，7.43(1H，dd，J＝12.5，2.5)，7.55(1H，t，J＝8.0)，7.68(1H，m)，7.73(1H，d，J＝8.0)，7.88(1H，bs)；
IR(KBr，cm -1)：1737，1675。
(b) N-(4-(1-acetimidoyl piperidin-4-yl oxygen)-3-fluorophenyl)-N-(3-(3-carbamimido-phenyl)-2-(E)-propenyl) sulphonamide ethyl acetate dihydrochloride
N-(3-(3-carbamimido-phenyl)-2-(E)-propenyl)-N-(3-fluoro-4-(piperidin-4-yl oxygen) phenyl) sulphonamide ethyl acetate dihydrochloride (467mg) is dissolved in the ethanol (25ml), add iminoester hydrochloride (293mg) and triethylamine (0.550ml), then at room temperature stirred 66 hours.In reaction mixture, add 4M hydrogenchloride dioxane solution (1.5ml), then concentrating under reduced pressure.(YMC-Pack ODS YMC, elutriant: 22% acetonitrile solution) refining, the gained amorphous solid is dissolved in the methyl alcohol (15ml) residue, adds 4M hydrogenchloride dioxane solution (0.3ml), then is evaporated to dried with preparative HPLC.In the gained amorphous solid water-soluble (approximately 15ml), after lyophilize, obtain colourless amorphous solid title compound 284mg (yield 57%).
1H?NMR(500MHz，DMSO-d 6)δppm：1.22(3H，t，J＝7.0)，1.68-1.82(2H，m)，2.06(2H，m)，2.31(3H，s)，3.51(1H，m)，3.59(1H，m)，3.71(1H，m)，3.86(1H，m)，4.19(2H，q，J＝7.0)，4.42(2H，s)，4.47(2H，d，J＝6.0)，4.76(1H，m)，6.46(1H，dt，J＝15.5，6.0)，6.57(1H，d，J＝15.5)，7.26(1H，d，J＝9.0)，7.35(1H，t，J＝9.0)，7.43(1H，dd，J＝12.0，2.5)，7.54(1H，t，J＝8.0)，7.73(2H，m)，7.95(1H，s)；
IR(KBr，cm -1)：1738，1673，1623。
Embodiment 11
N-(4-(1-acetimidoyl piperidin-4-yl oxygen)-3-fluorophenyl)-N-(3-(3-carbamimido-phenyl)-2-(E)-propenyl) sulphonamide acetic acid dihydrochloride (exemplary compounds number: 1941)
N-(4-(1-acetimidoyl piperidin-4-yl oxygen)-3-fluorophenyl)-N-(3-(3-carbamimido-phenyl)-2-(E)-propenyl) sulphonamide ethyl acetate dihydrochloride (199mg) is dissolved in the 3M hydrochloric acid (7ml), stirs 2 hours at 80 ℃.Reaction mixture carries out concentrating under reduced pressure after being cooled to room temperature, residue preparative HPLC (YMC-PackODS YMC, elutriant: 15% acetonitrile solution) refining, the gained amorphous solid is dissolved in the methyl alcohol (10ml), add 4M hydrogenchloride dioxane solution (0.2ml), then under reduced pressure be concentrated into dried.Residue is dissolved in the water (approximately 10ml), obtains title compound 163mg (yield 86%) after lyophilize.
1H?NMR(500MHz，DMSO-d 6)δppm：1.77(2H，m)，2.05(2H，m)，2.29(3H，s)，3.52(2H，m)，3.71(1H，m)，3.80(1H，m)，4.23(2H，s)，4.47(2H，d，J＝6.0)，4.73(1H，m)，6.44(1H，dt，J＝16.0，6.0)，6.57(1H，d，J＝16.0)，7.26(1H，m)，7.32(1H，t，J＝8.5)，7.43(1H，dd，J＝13.0，2.0)，7.55(1H，t，J＝8.0)，7.68(1H，d，J＝8.0)，7.72(1H，d，J＝8.0)，7.88(1H，s)；
IR(KBr，cm -1)：3295，1733，1673，1624。
Embodiment 12
N-(4-(1-acetimidoyl piperidin-4-yl oxygen) phenyl)-N-(3-(5-amidino groups-2-aminomethyl phenyl)-2-(E)-propenyl) sulphonamide ethyl acetate dihydrochloride (exemplary compounds number: 1771)
(a) N-(3-(5-amidino groups-2-aminomethyl phenyl)-2-(E)-propenyl)-N-(4-(piperidin-4-yl oxygen) phenyl) sulphonamide ethyl acetate dihydrochloride
N-(4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen) phenyl)-N-(3-(5-cyano group-2-aminomethyl phenyl)-2-(E)-propenyl) sulphonamide ethyl acetate (2.03g) is dissolved in the mixed solvent of methylene dichloride (40ml) and ethanol (40ml), passed into hydrogenchloride 1 hour under ice-cooled, the gained mixture at room temperature stirred in the reactor of jam-pack 6 hours.With the reaction mixture concentrating under reduced pressure, the gained residue is dissolved in the ethanol (45ml), adds aqueous ammonium chloride solution (0.36g is dissolved in the 15ml water) and 28% ammoniacal liquor (0.68ml), then at room temperature places 12 hours.With the reaction mixture concentrating under reduced pressure, residue is dissolved in the methyl alcohol (30ml), adds 4M hydrogenchloride dioxane solution (2ml), then concentrating under reduced pressure.Residue preparative HPLC (YMC-Pack ODS YMC, elutriant: 20% acetonitrile solution) refining, the amorphous solid that obtains is dissolved in the methyl alcohol (20ml), adds 4M hydrogenchloride ethyl acetate solution (1ml), then under reduced pressure is concentrated into dried.Obtain colourless amorphous solid title compound 1.49g (yield 75%).
1H?NMR(500MHz，DMSO-d 6)δppm：1.23(3H，t，J＝7.0)，1.82(2H，m)，2.09(2H，m)，2.22(3H，s)，3.05(2H，m)，3.21(2H，m)，4.19(2H，q，J＝7.0)，4.34(2H，s)，4.46(2H，d，J＝6.5)，4.66(1H，m)，6.30(1H，dt，J＝16.0，6.5)，6.66(1H，d，J＝16.0)，7.05(2H，d，J＝9.5)，7.37(1H，d，J＝7.5)，7.38(2H，d，J＝9.5)，7.61(1H，dd，J＝7.5，2.0)，7.86(1H，d，J＝2.0)；
IR(KBr，cm -1)：1738，1674。
(b) N-(4-(1-acetimidoyl piperidin-4-yl oxygen) phenyl)-N-(3-(5-amidino groups-2-aminomethyl phenyl)-2-(E)-propenyl) sulphonamide ethyl acetate dihydrochloride
N-(3-(5-amidino groups-2-aminomethyl phenyl)-2-(E)-propenyl)-N-(4-(piperidin-4-yl oxygen) phenyl) sulphonamide ethyl acetate dihydrochloride (1.43g) is dissolved in the ethanol (40ml), add iminoester hydrochloride (0.60g) and triethylamine (1.4ml), then at room temperature stirred 13 hours.In reaction mixture, add 4M hydrogenchloride ethyl acetate solution (2ml), then concentrating under reduced pressure.(YMC-Pack ODS YMC, elutriant: 25% acetonitrile solution) refining, the gained amorphous solid is dissolved in the methyl alcohol (20ml) residue, adds 4M hydrogenchloride ethyl acetate solution (0.8ml), then is evaporated to dried with preparative HPLC.Obtain colourless amorphous solid title compound 1.18mg (yield 77%).
1H?NMR(500MHz，DMSO-d 6)δppm：1.23(3H，t，J＝7.0)，1.67-1.80(2H，m)，2.05(2H，m)，2.22(3H，s)，2.30(3H，s)，3.49-3.61(2H，m)，3.72(1H，m)，3.83(1H，m)，4.19(2H，q，J＝7.0)，4.35(2H，s)，4.46(2H，d，J＝6.0)，4.72(1H，m)，6.32(1H，dt，J＝16.0，6.0)，6.66(1H，d，J＝16.0)，7.06(2H，d，J＝9.5)，7.38(1H，d，J＝9.0)，7.39(2H，d，J＝9.5)，7.64(1H，dd，J＝9.0，2.0)，7.88(1H，d，J＝2.0)；
IR(KBr，cm -1)：1738，1675，1626。
Embodiment 13
N-(4-(1-acetimidoyl piperidin-4-yl oxygen)-3-trifluoromethyl)-N-(3-(3-carbamimido-phenyl)-2-(E)-propenyl) sulphonamide ethyl acetate dihydrochloride (exemplary compounds number: 1440)
(a) N-(3-(3-carbamimido-phenyl)-2-(E)-propenyl)-N-(4-(piperidin-4-yl oxygen)-3-trifluoromethyl) sulphonamide ethyl acetate dihydrochloride
N-(4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-3-trifluoromethyl)-N-(3-(3-cyano-phenyl)-2-(E)-propenyl) sulphonamide ethyl acetate (2.06g) is dissolved in the mixed solvent of methylene dichloride (50ml) and ethanol (25ml), passed into hydrogenchloride 1 hour under ice-cooled, the gained mixture at room temperature stirred in the reactor of jam-pack 6 hours.With the reaction mixture concentrating under reduced pressure, the gained residue is dissolved in the ethanol (45ml), adds aqueous ammonium chloride solution (0.34g is dissolved in the 15ml water) and 28% ammoniacal liquor (0.63ml), then at room temperature places 12 hours.With the reaction mixture concentrating under reduced pressure, residue is dissolved in the methyl alcohol (30ml), adds 4M hydrogenchloride dioxane solution (2.5ml), then concentrating under reduced pressure.Residue preparative HPLC (YMC-Pack ODS YMC, elutriant: 25% acetonitrile solution) refining, the amorphous solid that obtains is dissolved in the methyl alcohol (20ml), adds 4M hydrogenchloride dioxane solution (0.5ml), then under reduced pressure is concentrated into dried.Obtain colourless amorphous solid title compound 1.21g (yield 60%).
1H?NMR(500MHz，DMSO-d 6)δppm：1.22(3H，t，J＝7.0)，1.87(2H，m)，2.08(2H，m)，3.11(2H，m)，3.33(2H，m)，4.18(2H，q，J＝7.0)，4.44(2H，s)，4.50(2H，d，J＝6.5)，4.89(1H，m)，6.44(1H，dt，J＝16.0，6.5)，6.57(1H，d，J＝16.0)，7.39(1H，d，J＝9.0)，7.55(1H，t，J＝8.0)，7.66-7.73(4H，m)，7.85(1H，s)；
IR(KBr，cm -1)：1738，1676。
(b) N-(4-(1-acetimidoyl piperidin-4-yl oxygen)-3-trifluoromethyl)-N-(3-(3-carbamimido-phenyl)-2-(E)-propenyl) sulphonamide ethyl acetate dihydrochloride
N-(3-(3-carbamimido-phenyl)-2-(E)-propenyl)-N-(4-(piperidin-4-yl oxygen)-3-trifluoromethyl) sulphonamide ethyl acetate dihydrochloride (1.13g) is dissolved in the ethanol (20ml), add iminoester hydrochloride (0.65mg) and triethylamine (1.20ml), then at room temperature stirred 13 hours.In reaction mixture, add 4M hydrogenchloride dioxane solution (2ml), then concentrating under reduced pressure.(YMC-Pack ODS YMC, elutriant: 30% acetonitrile solution) refining, the gained amorphous solid is dissolved in the methyl alcohol (20ml) residue, adds 4M hydrogenchloride ethyl acetate solution (0.5ml), then is evaporated to dried with preparative HPLC.Obtain colourless amorphous solid title compound 1.04g (yield 87%).
1H?NMR(500MHz，DMSO-d 6)δppm：1.22(3H，t，J＝7.0)，1.81(2H，m)，2.07(2H，m)，2.30(3H，s)，3.59-3.73(4H，m)，4.19(2H，q，J＝7.0)，4.46(2H，s)，4.50(2H，d，J＝6.5)，4.96(1H，m)，6.47(1H，dt，J＝16.5，6.5)，6.58(1H，d，J＝16.5)，7.44(1H，d，J＝9.5)，7.56(1H，t，J＝8.0)，7.71(4H，m)，7.90(1H，s)；
IR(KBr，cm -1)：1739，1673，1618。
Embodiment 14
N-(4-(1-acetimidoyl piperidin-4-yl oxygen)-3-aminomethyl phenyl)-N-(3-(3-carbamimido-phenyl)-2-(E)-propenyl) sulphonamide ethyl acetate dihydrochloride (exemplary compounds number: 1420)
(a) N-(3-(3-carbamimido-phenyl)-2-(E)-propenyl)-N-(3-methyl-4-(piperidin-4-yl oxygen) phenyl) sulphonamide ethyl acetate dihydrochloride
N-(4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-3-aminomethyl phenyl)-N-(3-(3-cyano-phenyl)-2-(E)-propenyl) sulphonamide ethyl acetate (1.90g) is dissolved in the mixed solvent of methylene dichloride (40ml) and ethanol (40ml), passed into hydrogenchloride 1 hour under ice-cooled, the gained mixture at room temperature stirred in the reactor of jam-pack 5 hours.With the reaction mixture concentrating under reduced pressure, the gained residue is dissolved in the ethanol (45ml), adds aqueous ammonium chloride solution (0.34g is dissolved in the 15ml water) and 28% ammoniacal liquor (0.64ml), then at room temperature places 13 hours.With the reaction mixture concentrating under reduced pressure, residue is dissolved in the methyl alcohol (20ml), adds 4M hydrogenchloride ethyl acetate solution (2ml), then concentrating under reduced pressure.Residue preparative HPLC (YMC-Pack ODS YMC, elutriant: 20% acetonitrile solution) refining, the amorphous solid that obtains is dissolved in the methyl alcohol (20ml), adds 4M hydrogenchloride ethyl acetate solution (1ml), then under reduced pressure is concentrated into dried.Obtain colourless amorphous solid title compound 1.36 (yield 73%).
1H?NMR(400MHz，DMSO-d 6)δppm：1.23(3H，t，J＝7.0)，1.87(2H，m)，2.10(2H，m)，2.17(3H，s)，3.07(2H，m)，3.17(2H，m)，4.20(2H，q，J＝7.0)，4.33(2H，s)，4.44(2H，d，J＝6.0)，4.65(1H，m)，6.44(1H，dt，J＝16.0，6.0)，6.56(1H，d，J＝16.0)，7.05(1H，d，J＝9.0)，7.24(1H，dd，J＝9.0，2.5)，7.29(1H，d，J＝2.5)，7.54(1H，t，J＝8.0)，7.71(2H，m)，7.90(1H，s)；
IR(KBr，cm -1)：1738，1675。
(b) N-(4-(1-acetimidoyl piperidin-4-yl oxygen)-3-aminomethyl phenyl)-N-(3-(3-carbamimido-phenyl)-2-(E)-propenyl) sulphonamide ethyl acetate dihydrochloride
N-(3-(3-carbamimido-phenyl)-2-(E)-propenyl)-N-(3-methyl-4-(piperidin-4-yl oxygen) phenyl) sulphonamide ethyl acetate dihydrochloride (1.23g) is dissolved in the ethanol (40ml), add iminoester hydrochloride (0.52g) and triethylamine (1.20ml), then at room temperature stirred 13 hours.In reaction mixture, add 4M hydrogenchloride dioxane solution (2ml), then concentrating under reduced pressure.(YMC-Pack ODS YMC, elutriant: 22% acetonitrile solution) refining, the gained amorphous solid is dissolved in the methyl alcohol (20ml) residue, adds 4M hydrogenchloride ethyl acetate solution (0.6ml), then is evaporated to dried with preparative HPLC.Obtain colourless amorphous solid title compound 1.10g (yield 84%).
1H?NMR(500MHz，DMSO-d 6)δppm：1.24(3H，t，J＝7.0)，1.77(2H，m)，2.03(2H，m)，2.16(3H，s)，2.30(3H，s)，3.60-3.80(4H，m)，4.20(2H，q，J＝7.0)，4.33(2H，s)，4.44(2H，d，J＝6.0)，4.73(1H，m)，6.45(1H，dt，J＝16.0，6.0)，6.56(1H，d，J＝16.0)，7.06(1H，d，J＝9.0)，7.25(1H，dd，J＝9.0，2.5)，7.29(1H，d，J＝2.5)，7.55(1H，t，J＝8.0)，7.71(2H，m)，7.91(1H，s)；
IR(KBr，cm -1)：1738，1672，1624。
Embodiment 15
N-(4-(1-acetimidoyl piperidin-4-yl oxygen) phenyl)-N-(3-(3-amidino groups-5-aminomethyl phenyl)-2-(E)-propenyl) sulphonamide ethyl acetate dihydrochloride (exemplary compounds number: 1711)
(a) N-(3-(3-amidino groups-5-aminomethyl phenyl)-2-(E)-propenyl)-N-(4-(piperidin-4-yl oxygen) phenyl) sulphonamide ethyl acetate dihydrochloride
N-(4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen) phenyl)-N-(3-(3-cyano group-5-aminomethyl phenyl)-2-(E)-propenyl) sulphonamide ethyl acetate (1.59g) is dissolved in the mixed solvent of methylene dichloride (15ml) and ethanol (15ml), passed into hydrogenchloride 1 hour under ice-cooled, the gained mixture at room temperature stirred in the reactor of jam-pack 4 hours.With the reaction mixture concentrating under reduced pressure, the gained residue is dissolved in the ethanol (20ml), adds aqueous ammonium chloride solution (0.21g is dissolved in the 4ml water) and 28% ammoniacal liquor (0.53ml), then at room temperature places and spends the night.With the reaction mixture concentrating under reduced pressure, and the residue preparative HPLC (YMC-Pack ODS YMC, elutriant: 20% acetonitrile solution) refining, obtain colourless amorphous solid title compound 1.10g (yield 80%).
1H?NMR(270MHz，DMSO-d 6)δppm：1.23(3H，t，J＝7.0)，1.85(2H，m)，2.10(2H，m)，2.36(3H，s)，3.06(2H，m)，3.18(2H，m)，4.19(2H，q，J＝7.0)，4.33(2H，s)，4.44(2H，d，J＝5.5)，4.66(1H，m)，6.41(1H，dt，J＝16.0，5.5)，6.51(1H，d，J＝16.0)，7.04(2H，d，J＝9.0)，7.38(2H，d，J＝9.0)，7.54(1H，s)，7.58(1H，s)，7.68(1H，s)；
IR(KBr，cm -1)：1737，1674。
(b) N-(4-(1-acetimidoyl piperidin-4-yl oxygen) phenyl)-N-(3-(3-amidino groups-5-aminomethyl phenyl)-2-(E)-propenyl) sulphonamide ethyl acetate dihydrochloride
N-(3-(3-amidino groups-5-aminomethyl phenyl)-2-(E)-propenyl)-N-(4-(piperidin-4-yl oxygen) phenyl) sulphonamide ethyl acetate dihydrochloride (800mg) is dissolved in the ethanol (25ml), add iminoester hydrochloride (1400mg) and triethylamine (2.2ml), then at room temperature stirred 27 hours.With the reaction mixture concentrating under reduced pressure, the residue preparative HPLC (YMC-Pack ODS YMC, elutriant: 20% acetonitrile solution) refining, the gained amorphous solid is dissolved in the ethanol (20ml), add 4M hydrogenchloride ethyl acetate solution (1ml), then be evaporated to dried.The gained amorphous solid is suspended in the ethyl acetate, obtains colourless amorphous solid title compound 400mg (yield 41%) after the filtration.
1H?NMR(270MHz，DMSO-d 6)δppm：1.23(3H，t，J＝7.0)，1.70(2H，m)，2.05(2H，m)，2.30(3H，s)，2.36(3H，s)，3.45-3.65(2H，m)，3.65-3.95(2H，m)，4.19(2H，q，J＝7.0)，4.34(2H，s)，4.44(2H，d，J＝5.5)，4.71(1H，m)，6.41(1H，dt，J＝16.0，5.5)，6.51(1H，d，J＝16.0)，7.04(2H，d，J＝9.0)，7.39(2H，d，J＝9.0)，7.56(2H，containing?two?singlets)，7.70(1H，s)；
IR(KBr，cm -1)：1738，1672，1625。
Embodiment 16
N-(4-(1-acetimidoyl piperidin-4-yl oxygen) phenyl)-N-(3-(3-amidino groups-5-aminomethyl phenyl)-2-(E)-propenyl) sulphonamide acetic acid dihydrochloride (exemplary compounds number: 2208)
N-(4-(1-acetimidoyl piperidin-4-yl oxygen) phenyl)-N-(3-(3-amidino groups-5-aminomethyl phenyl)-2-(E)-propenyl) sulphonamide ethyl acetate dihydrochloride (200mg) is dissolved in the 1M hydrochloric acid (8ml), stirs 8 hours at 80 ℃.With the reaction mixture concentrating under reduced pressure, residue preparative HPLC (YMC-Pack ODSYMC, elutriant: 20% acetonitrile solution) refining, the gained amorphous solid is soluble in water, add 4M hydrogenchloride ethyl acetate solution (0.2ml), then under reduced pressure be concentrated into driedly, obtain colourless amorphous solid title compound 110mg (yield 57%).
1H?NMR(270MHz，DMSO-d 6)δppm：1.60-1.85(2H，m)，2.05(2H，m)，2.30(3H，s)，2.36(3H，s)，3.40-3.65(2H，m)，3.65-3.95(2H，m)，4.20(2H，s)，4.44(2H，d，J＝5.0)，4.70(1H，m)，6.41(1H，dt，J＝16.0，5.0)，6.51(1H，d，J＝16.0)，7.04(2H，d，J＝9.0)，7.39(2H，d，J＝9.0)，7.55(2H，containing?twosinglets)，7.69(1H，s)；
MS(FAB)m/z＝528(M+H) +。
Embodiment 17
N-(4-(1-acetimidoyl piperidin-4-yl oxygen) phenyl)-N-(3-(3-amidino groups-4-fluorophenyl)-2-(E)-propenyl) sulphonamide ethyl acetate dihydrochloride (exemplary compounds number: 1638)
(a) N-(3-(3-amidino groups-4-fluorophenyl)-2-(E)-propenyl)-N-(4-(piperidin-4-yl oxygen) phenyl) sulphonamide ethyl acetate dihydrochloride
N-(4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen) phenyl)-N-(3-(3-cyano group-4-fluorophenyl)-2-(E)-propenyl) sulphonamide ethyl acetate (1530mg) is dissolved in the mixed solvent of methylene dichloride (15ml) and ethanol (15ml), passed into hydrogenchloride 1.25 hours under ice-cooled, the gained mixture at room temperature stirred in the reactor of jam-pack 4 hours.With the reaction mixture concentrating under reduced pressure, the gained residue is dissolved in the ethanol (20ml), adds aqueous ammonium chloride solution (200mg is dissolved in the 4ml water) and 28% ammoniacal liquor (0.50ml), then at room temperature places and spends the night.With the reaction mixture concentrating under reduced pressure, and the residue preparative HPLC (YMC-Pack ODS YMC, elutriant: 20% acetonitrile solution) refining, obtain colourless amorphous solid title compound 550mg (yield 41%).
1H?NMR(270MHz，DMSO-d 6)δppm：1.23(3H，t，J＝7.0)，1.75-1.95(2H，m)，2.00-2.20(2H，m)，2.95-3.15(2H，m)，3.15-3.30(2H，m)，4.19(2H，q，J＝7.0)，4.33(2H，s)，4.42(2H，d，J＝6.0)，4.65(1H，m)，6.35(1H，dt，J＝16.0，6.0)，6.53(1H，d，J＝16.0)，7.03(2H，d，J＝9.0)，7.38(2H，d，J＝9.0)，7.42(1H，m)，7.73(2H，m)；
IR(KBr，cm -1)：1737，1677。
(b) N-(4-(1-acetimidoyl piperidin-4-yl oxygen) phenyl)-N-(3-(3-amidino groups-4-fluorophenyl)-2-(E)-propenyl) sulphonamide ethyl acetate dihydrochloride
N-(3-(3-amidino groups-4-fluorophenyl)-2-(E)-propenyl)-N-(4-(piperidin-4-yl oxygen) phenyl) sulphonamide ethyl acetate dihydrochloride (350mg) is dissolved in the ethanol (14ml), add iminoester hydrochloride (160mg) and triethylamine (0.36ml), then at room temperature stirred 6 hours.With the reaction mixture concentrating under reduced pressure, the residue preparative HPLC (YMC-Pack ODS YMC, elutriant: 20% acetonitrile solution) refining, the gained amorphous solid is dissolved in the ethanol (8ml), add 4M hydrogenchloride ethyl acetate solution (0.5ml), then be evaporated to dried.Obtain colourless amorphous solid title compound 279mg (yield 65%).
1H?NMR(270MHz，DMSO-d 6)δppm：1.23(3H，t，J＝7.0)，1.73(2H，m)，2.05(2H，m)，2.29(3H，s)，3.40-3.65(2H，m)，3.65-3.90(2H，m)，4.19(2H，q，J＝7.0)，4.33(2H，s)，4.42(2H，d，J＝5.5)，4.71(1H，m)，6.35(1H，dt，J＝16.0，5.5)，6.54(1H，d，J＝16.0)，7.04(2H，d，J＝9.0)，7.38(2H，d，J＝9.0)，7.40(1H，m)，7.73(2H，m)；
IR(KBr，cm -1)：1738，1675，1618。
Embodiment 18
N-(4-(1-acetimidoyl piperidin-4-yl oxygen) phenyl)-N-(3-(3-carbamimido-phenyl)-2-(E)-propenyl) ethanamide dihydrochloride (exemplary compounds number: 948)
(a) N-(3-(3-carbamimido-phenyl)-2-(E)-propenyl)-N-(4-(piperidin-4-yl oxygen) phenyl) ethanamide dihydrochloride
N-(4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen) phenyl)-N-(3-(3-cyano-phenyl)-2-(E)-propenyl) ethanamide (1203mg) is dissolved in the mixed solvent of methylene dichloride (60ml) and ethanol (30ml), passed into hydrogenchloride 1 hour under ice-cooled, the gained mixture at room temperature stirred in the reactor of jam-pack 7 hours.With the reaction mixture concentrating under reduced pressure, the gained residue is dissolved in the ethanol (50ml), adds aqueous ammonium chloride solution (271mg is dissolved in the 25ml water) and 28% ammoniacal liquor (0.51ml), then at room temperature places 12 hours.In reaction mixture, add 4M hydrogenchloride dioxane solution (1.5ml), then concentrating under reduced pressure.Residue preparative HPLC (YMC-Pack ODS YMC, elutriant: 13% acetonitrile solution) refining, the amorphous solid that obtains is dissolved in the methyl alcohol (10ml), adds 4M hydrogenchloride dioxane solution (1.5ml), then under reduced pressure is concentrated into dried.In the gained amorphous solid water-soluble (approximately 10ml), after lyophilize, obtain faint yellow amorphous solid title compound 853mg (yield 72%).
1H?NMR(270MHz，DMSO-d 6)δppm：1.78(3H，s)，1.83(2H，m)，2.11(2H，m)，2.90-3.30(4H，m)，4.39(2H，m)，4.50-4.80(1H，m)，6.40-6.60(2H，m)，7.04(2H，d，J＝9.0)，7.28(2H，d，J＝9.0)，7.55(1H，t，J＝7.5)，7.71(1H，d，J＝7.5)，7.73(1H，d，J＝7.5)，7.94(1H，s)；
IR(KBr，cm -1)：1675，1626。
(b) N-(4-(1-acetimidoyl piperidin-4-yl oxygen) phenyl)-N-(3-(3-carbamimido-phenyl)-2-(E)-propenyl) ethanamide dihydrochloride
N-(3-(3-carbamimido-phenyl)-2-(E)-propenyl)-N-(4-(piperidin-4-yl oxygen) phenyl) ethanamide dihydrochloride (400mg) is dissolved in the methyl alcohol (20ml), at room temperature add iminoester hydrochloride (320mg) and triethylamine (0.60ml), then under same temperature, stirred 12 hours.In reaction mixture, add 4M hydrogenchloride dioxane solution (1ml), then concentrating under reduced pressure.(YMC-Pack ODSYMC, elutriant: 15% acetonitrile solution) refining, the gained amorphous solid is dissolved in the methyl alcohol (10ml) residue, adds 4M hydrogenchloride dioxane solution (0.5ml), then is evaporated to dried with preparative HPLC.In the gained amorphous solid water-soluble (approximately 10ml), after lyophilize, obtain colourless amorphous solid title compound 342mg (yield 79%).
1H?NMR(270MHz，DMSO-d 6)δppm：1.74(2H，m)，1.78(3H，s)，2.04(2H，m)，2.31(3H，s)，3.45-3.95(4H，m)，4.39(2H，m)，4.60-4.80(1H，m)，6.40-6.60(2H，m)，7.05(2H，d，J＝8.5)，7.28(2H，d，J＝8.5)，7.55(1H，t，J＝7.5)，7.65-7.80(2H，m)，7.95(1H，s)；
IR(KBr，cm -1)：1672，1624。
Embodiment 19
N-(4-(1-acetimidoyl piperidin-4-yl oxygen) phenyl)-N-(3-(3-carbamimido-phenyl)-2-(E)-propenyl)-2-hydroxyl acetamide dihydrochloride (exemplary compounds number: 1014)
(a) N-(3-(3-carbamimido-phenyl)-2-(E)-propenyl)-N-(4-(piperidin-4-yl oxygen) phenyl)-2-hydroxyl acetamide dihydrochloride
N-(4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen) phenyl)-N-(3-(3-cyano-phenyl)-2-(E)-propenyl)-2-hydroxyl acetamide (799mg) is dissolved in the mixed solvent of methylene dichloride (30ml) and ethanol (15ml), passed into hydrogenchloride 1 hour under ice-cooled, the gained mixture at room temperature stirred in the reactor of jam-pack 7 hours.With the reaction mixture concentrating under reduced pressure, the gained residue is dissolved in the ethanol (20ml), adds aqueous ammonium chloride solution (213mg is dissolved in the 10ml water) and 28% ammoniacal liquor (0.40ml), then at room temperature places 12 hours.In reaction mixture, add 4M hydrogenchloride dioxane solution (1ml), then concentrating under reduced pressure.Residue preparative HPLC (YMC-Pack ODS YMC, elutriant: 11% acetonitrile solution) refining, the amorphous solid that obtains is dissolved in the methyl alcohol (10ml), adds 4M hydrogenchloride dioxane solution (0.5ml), then under reduced pressure is concentrated into dried.In the gained amorphous solid water-soluble (approximately 70ml), after lyophilize, obtain colourless amorphous solid title compound 685mg (yield 72%).
1H?NMR(270MHz，DMSO-d 6)δppm：1.84(2H，m)，2.10(2H，m)，2.90-3.80(6H，m)，4.36(2H，m)，4.65(1H，m)，6.50(2H，m)，7.03(2H，d，J＝8.5)，7.28(2H，d，J＝8.5)，7.55(1H，t，J＝7.5)，7.65-7.80(2H，m)，7.92(1H，s)；
IR(KBr，cm -1)：1673。
(b) N-(4-(1-acetimidoyl piperidin-4-yl oxygen) phenyl)-N-(3-(3-carbamimido-phenyl)-2-(E)-propenyl)-2-hydroxyl acetamide dihydrochloride
N-(3-(3-carbamimido-phenyl)-2-(E)-propenyl)-N-(4-(piperidin-4-yl oxygen) phenyl)-2-hydroxyl acetamide dihydrochloride (385mg) is dissolved in the methyl alcohol (20ml), at room temperature add iminoester hydrochloride (300mg) and triethylamine (0.56ml), then under same temperature, stirred 12 hours.In reaction mixture, add 4M hydrogenchloride dioxane solution (1ml), then concentrating under reduced pressure.(YMC-Pack ODS YMC, elutriant: 14% acetonitrile solution) refining, the gained amorphous solid is dissolved in the methyl alcohol (10ml) residue, adds 4M hydrogenchloride dioxane solution (0.5ml), then is evaporated to dried with preparative HPLC.In the gained amorphous solid water-soluble (approximately 10ml), after lyophilize, obtain colourless amorphous solid title compound 336mg (yield 80%).
1H?NMR(270MHz，DMSO-d 6)δppm：1.73(2H，m)，2.05(2H，m)，2.30(3H，s)，3.30-3.90(6H，m)，4.39(2H，m)，4.69(1H，m)，6.40-6.60(2H，m)，7.04(2H，d，J＝9.0)，7.28(2H，d，J＝9.0)，7.55(1H，t，J＝8.0)，7.65-7.80(2H，m)，7.93(1H，s)；
IR(KBr，cm -1)：1671。
Embodiment 20
3-(3-(N-(4-(1-acetimidoyl piperidin-4-yl oxygen) phenyl)-N-benzylamino)-1-(E)-propenyl) benzenyl amidine tri hydrochloride (exemplary compounds number: 864)
(a) 3-(3-(N-benzyl-N-(4-(piperidin-4-yl oxygen) phenyl) amino)-1-(E)-propenyl) benzenyl amidine tri hydrochloride
3-(3-(N-benzyl-N-(4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen) phenyl) amino)-1-(E)-propenyl) benzonitrile (916mg) is dissolved in the mixed solvent of methylene dichloride (30ml) and ethanol (15ml), passed into hydrogenchloride 1 hour under ice-cooled, the gained mixture at room temperature stirred in the reactor of jam-pack 7 hours.With the reaction mixture concentrating under reduced pressure, residue is dissolved in the ethanol (20ml), adds aqueous ammonium chloride solution (187mg is dissolved in the 10ml water) and 28% ammoniacal liquor (0.46ml), then at room temperature places 12 hours.Add 4M hydrogenchloride dioxane solution (1ml) in the reaction mixture, concentrating under reduced pressure then, residue is with silica gel column chromatography (Cosmosil (registered trademark) 75C18-PREP; NacalaiTesque, elutriant: 5% acetonitrile solution) refining, the amorphous solid that obtains is dissolved in the methyl alcohol (10ml), adds 4M hydrogenchloride dioxane solution (0.5ml), then under reduced pressure is concentrated into dried.In the gained amorphous solid water-soluble (approximately 10ml), after lyophilize, obtain light brown amorphous solid title compound 581mg (yield 60%).
1H?NMR(500MHz，DMSO-d 6)δppm：1.78(2H，m)，2.03(2H，m)，2.98(2H，m)，3.15(2H，m)，4.35(2H，m)，4.50(1H，m)，4.76(2H，m)，6.61(1H，dt，J＝16.0，6.5)，6.70(1H，d，J＝16.0)，6.93(2H，m)，7.20-7.35(3H，m)，7.35-7.50(4H，m)，7.57(1H，t，J＝8.0)，7.70(1H，d，J＝8.0)，7.73(1H，d，J＝8.0)，7.89(1H，s)；
IR(KBr，cm -1)：1675。
(b) 3-(3-(N-(4-(1-acetimidoyl piperidin-4-yl oxygen) phenyl)-N-benzylamino)-1-(E)-propenyl) benzenyl amidine tri hydrochloride
3-(3-(N-benzyl-N-(4-(piperidin-4-yl oxygen) phenyl) amino)-1-(E)-propenyl) benzenyl amidine tri hydrochloride (335mg) is dissolved in the methyl alcohol (20ml), at room temperature add iminoester hydrochloride (230mg) and triethylamine (0.51ml), then under same temperature, stirred 12 hours.In reaction mixture, add 4M hydrogenchloride dioxane solution (1ml), then concentrating under reduced pressure, residue preparative HPLC (YMC-Pack ODSYMC, elutriant: 30% acetonitrile solution) refining, the gained amorphous solid is dissolved in the methyl alcohol (10ml), add 4M hydrogenchloride dioxane solution (0.5ml), then be evaporated to dried.In the gained amorphous solid water-soluble (approximately 10ml), after lyophilize, obtain colourless amorphous solid title compound 252mg (yield 70%).
1H?NMR(270MHz，DMSO-d 6)δppm：1.50-1.75(2H，m)，1.96(2H，m)，2.29(3H，s)，3.40-3.90(4H，m)，4.40(2H，m)，4.50-4.90(3H，m)，6.63(1H，dt，J＝16.0，6.0)，6.74(1H，d，J＝16.0)，6.97(2H，d，J＝8.5)，7.15-7.30(3H，m)，7.40-7.60(4H，m)，7.56(1H，t，J＝7.5)，7.66(1H，d，J＝7.5)，7.77(1H，d，J＝7.5)，7.92(1H，s)；
IR(KBr，cm -1)：1672，1624.
Embodiment 21
3-(3-(N-(4-(1-acetimidoyl piperidin-4-yl oxygen) phenyl) amino)-1-(E)-propenyl) benzenyl amidine tri hydrochloride (exemplary compounds number: 177)
(a) 3-(3-(N-(4-(piperidin-4-yl oxygen) phenyl) amino)-1-(E)-propenyl) benzenyl amidine tri hydrochloride
3-(3-(N-(4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen) phenyl) amino)-1-(E)-propenyl) benzonitrile (900mg) is dissolved in the mixed solvent of methylene dichloride (30ml) and ethanol (15ml), passed into hydrogenchloride 1 hour under ice-cooled, the gained mixture at room temperature stirred in the reactor of jam-pack 7 hours.With the reaction mixture concentrating under reduced pressure, residue is dissolved in the ethanol (20ml), adds aqueous ammonium chloride solution (222mg is dissolved in the 10ml water) and 28% ammoniacal liquor (0.54ml), then at room temperature places 12 hours.In reaction mixture, add 4M hydrogenchloride dioxane solution (1ml), then concentrating under reduced pressure, residue preparative HPLC (YMC-Pack ODS YMC, elutriant: 15% acetonitrile solution) refining, the amorphous solid that obtains is dissolved in the methyl alcohol (10ml), add 4M hydrogenchloride dioxane solution (0.5ml), then under reduced pressure be concentrated into dried.Obtain yellow amorphous solid title compound 735mg (yield 77%).
1H?NMR(500MHz，DMSO-d 6)δppm：1.82(2H，m)，2.05(2H，m)，3.03(2H，m)，3.20(2H，m)，3.95-4.10(2H，m)，4.50-4.65(1H，m)，6.55(1H，dt，J＝16.0，6.5)，6.79(1H，d，J＝16.0)，7.05(2H，m)，7.20-7.45(2H，m)，7.61(1H，t，J＝8.0)，7.70-7.80(2H，m)，7.87(1H，s)；
IR(KBr，cm -1)：1675。
(b) 3-(3-(N-(4-(1-acetimidoyl piperidin-4-yl oxygen) phenyl) amino)-1-(E)-propenyl) benzenyl amidine tri hydrochloride
3-(3-(N-(4-(piperidin-4-yl oxygen) phenyl) amino)-1-(E)-propenyl) benzenyl amidine tri hydrochloride (345mg) is dissolved in the methyl alcohol (20ml), at room temperature add iminoester hydrochloride (185mg) and triethylamine (0.52ml), then under same temperature, stirred 12 hours.In reaction mixture, add 4M hydrogenchloride dioxane solution (1ml), then concentrating under reduced pressure, residue preparative HPLC (YMC-Pack ODSYMC, elutriant: 30% acetonitrile solution) refining, the gained amorphous solid is dissolved in the methyl alcohol (10ml), add 4M hydrogenchloride dioxane solution (0.5ml), then be evaporated to dried.In the gained amorphous solid water-soluble (approximately 10ml), after lyophilize, obtain yellow amorphous solid title compound 272mg (yield 72%).
1H?NMR(270MHz，DMSO-d 6)δppm：1.73(2H，m)，2.05(2H，m)，2.30(s，3H)，3.40-3.95(4H，m)，4.06(2H，d，J＝6.5)，4.69(1H，m)，6.56(1H，dt，J＝16.0，6.5)，6.80(1H，d，J＝16.0)，7.10(2H，d，J＝9.0)，7.35-7.55(2H，m)，7.60(1H，t，J＝8.0)，7.70-7.80(2H，m)，7.87(1H，s)；
IR(KBr，cm -1)：1672，1625。
Embodiment 22
3-(3-(N-(4-(1-acetimidoyl piperidin-4-yl oxygen) phenyl)-N-isopropylamino)-1-(E)-propenyl) benzenyl amidine tri hydrochloride (exemplary compounds number: 358)
(a) 3-(3-(N-sec.-propyl-N-(4-(piperidin-4-yl oxygen) phenyl) amino)-1-(E)-propenyl) benzenyl amidine tri hydrochloride
3-(3-(N-(4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen) phenyl)-N-isopropylamino)-1-(E)-propenyl) benzonitrile (705mg) is dissolved in the mixed solvent of methylene dichloride (30ml) and ethanol (15ml), passed into hydrogenchloride 1 hour under ice-cooled, the gained mixture at room temperature stirred in the reactor of jam-pack 7 hours.With the reaction mixture concentrating under reduced pressure, residue is dissolved in the ethanol (20ml), adds aqueous ammonium chloride solution (159mg is dissolved in the 10ml water) and 28% ammoniacal liquor (0.39ml), then at room temperature places 12 hours.In reaction mixture, add 4M hydrogenchloride dioxane solution (1ml), then concentrating under reduced pressure, residue preparative HPLC (YMC-Pack ODS YMC, elutriant: 15% acetonitrile solution) refining, the amorphous solid that obtains is dissolved in the methyl alcohol (10ml), add 4M hydrogenchloride dioxane solution (0.5ml), then under reduced pressure be concentrated into dried, in the gained amorphous solid water-soluble (approximately 10ml), after lyophilize, obtain light brown amorphous solid title compound 570mg (yield 70%).
1H?NMR(270MHz，DMSO-d 6)δppm：1.16(3H，m)，1.40(3H，m)，1.82(2H，m)，2.07(2H，m)，3.03(2H，m)，3.18(2H，m)，3.98(1H，m)，4.41(2H，m)，4.68(1H，m)，6.40(1H，m)，6.72(1H，d，J＝16.0)，7.13(2H，m)，7.50-7.65(2H，m)，7.70-7.85(4H，m)；
IR(KBr，cm -1)：1675。
(b) 3-(3-(N-(4-(1-acetimidoyl piperidin-4-yl oxygen) phenyl)-N-isopropylamino)-1-(E)-propenyl) benzenyl amidine tri hydrochloride
3-(3-(N-sec.-propyl-N-(4-(piperidin-4-yl oxygen) phenyl) amino)-1-(E)-propenyl) benzenyl amidine tri hydrochloride (310mg) is dissolved in the methyl alcohol (20ml), at room temperature add iminoester hydrochloride (229mg) and triethylamine (0.52ml), then under same temperature, stirred 12 hours.In reaction mixture, add 4M hydrogenchloride dioxane solution (1ml), then concentrating under reduced pressure, residue preparative HPLC (YMC-Pack ODSYMC, elutriant: 15% acetonitrile solution) refining, the gained amorphous solid is dissolved in the methyl alcohol (10ml), add 4M hydrogenchloride dioxane solution (0.5ml), then be evaporated to dried.In the gained amorphous solid water-soluble (approximately 10ml), after lyophilize, obtain light brown amorphous solid title compound 259mg (yield 77%).
1H?NMR(270MHz，DMSO-d 6)δppm：1.17(3H，d，J＝6.0)，1.43(3H，d，J＝6.0)，1.70(2H，m)，2.04(2H，m)，2.31(3H，s)，3.45-4.05(5H，m)，4.41(2H，m)，4.74(1H，m)，6.42(1H，dt，J＝16.0，7.0)，6.73(1H，d，J＝16.0)，7.15(2H，d，J＝8.5)，7.50-7.65(2H，m)，7.70-7.90(4H，m)；
IR(KBr，cm -1)：1672，1623。
Embodiment 23
2-(N-(4-(1-acetimidoyl piperidin-4-yl oxygen) phenyl)-N-(3-(3-carbamimido-phenyl)-2-(E)-propenyl) amino) ethyl acetate tri hydrochloride (exemplary compounds number: 668)
(a) 2-(N-(3-(3-carbamimido-phenyl)-2-(E)-propenyl)-N-(4-(piperidin-4-yl oxygen) phenyl) amino) ethyl acetate tri hydrochloride
2-(N-(4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen) phenyl)-N-(3-(3-cyano-phenyl)-2-(E)-propenyl) amino) ethyl acetate (1305mg) is dissolved in the mixed solvent of methylene dichloride (30ml) and ethanol (15ml), passed into hydrogenchloride 1 hour under ice-cooled, the gained mixture at room temperature stirred in the reactor of jam-pack 7 hours.With the reaction mixture concentrating under reduced pressure, the gained residue is dissolved in the ethanol (20ml), adds aqueous ammonium chloride solution (269mg is dissolved in the 10ml water) and 28% ammoniacal liquor (0.66ml), then at room temperature places 12 hours.In reaction mixture, add 4M hydrogenchloride dioxane solution (1ml), then concentrating under reduced pressure.Residue preparative HPLC (YMC-Pack ODSYMC, elutriant: 20% acetonitrile solution) refining, the amorphous solid that obtains is dissolved in the methyl alcohol (10ml), adds 4M hydrogenchloride dioxane solution (0.5ml), then under reduced pressure is concentrated into dried.In the gained amorphous solid water-soluble (approximately 10ml), after lyophilize, obtain faint yellow amorphous solid title compound 652mg (yield 48%).
1H?NMR(270MHz，DMSO-d 6)δppm：1.18(3H，t，J＝7.0)，1.80(2H，m)，2.04(2H，m)，3.00(2H，m)，3.17(2H，m)，4.11(2H，q，J＝7.0)，4.10-4.20(4H，m)，4.42(1H，m)，6.55(1H，dt，J＝16.0，5.0)，6.65(2H，d，J＝9.0)，6.67(1H，d，J＝16.0)，6.87(2H，d，J＝9.0)，7.56(1H，t，J＝7.5)，7.65-7.80(2H，m)，7.91(1H，s)；
IR(KBr，cm -1)：1747，1675。
(b) 2-(N-(4-(1-acetimidoyl piperidin-4-yl oxygen) phenyl)-N-(3-(3-carbamimido-phenyl)-2-(E)-propenyl) amino) ethyl acetate tri hydrochloride
2-(N-(3-(3-carbamimido-phenyl)-2-(E)-propenyl)-N-(4-(piperidin-4-yl oxygen) phenyl) amino) ethyl acetate tri hydrochloride (400mg) is dissolved in the methyl alcohol (20ml), at room temperature add iminoester hydrochloride (270mg) and triethylamine (0.61ml), then under same temperature, stirred 12 hours.In reaction mixture, add 4M hydrogenchloride dioxane solution (1ml), then concentrating under reduced pressure.(YMC-Pack ODS YMC, elutriant: 24% acetonitrile solution) refining, the gained amorphous solid is dissolved in the methyl alcohol (10ml) residue, adds 4M hydrogenchloride dioxane solution (0.5ml), then is evaporated to dried with preparative HPLC.In the gained amorphous solid water-soluble (approximately 10ml), after lyophilize, obtain faint yellow amorphous solid title compound 350mg (yield 81%).
1H?NMR(270MHz，DMSO-d 6)δppm：1.18(3H，t，J＝7.0)，1.70(2H，m)，1.99(2H，m)，2.31(3H，s)，3.45-3.85(4H，m)，4.11(2H，q，J＝7.0)，4.15-4.25(4H，m)，4.48(1H，m)，6.56(1H，dt，J＝16.0，4.5)，6.66(2H，d，J＝9.0)，6.67(1H，d，J＝16.0)，6.88(2H，d，J＝9.0)，7.56(1H，t，J＝8.0)，7.65-7.80(2H，m)，7.92(1H，s)；
IR(KBr，cm -1)：1747，1672，1623。
Embodiment 24
3-(3-(N-(4-(1-acetimidoyl piperidin-4-yl oxygen) phenyl)-N-ethylamino)-1-(E)-propenyl) benzenyl amidine tri hydrochloride (exemplary compounds number: 297)
(a) 3-(3-(N-ethyl-N-(4-(piperidin-4-yl oxygen) phenyl) amino)-1-(E)-propenyl) benzenyl amidine tri hydrochloride
3-(3-(N-(4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen) phenyl)-N-ethylamino)-1-(E)-propenyl) benzonitrile (770mg) is dissolved in the mixed solvent of methylene dichloride (30ml) and ethanol (15ml), passed into hydrogenchloride 1 hour under ice-cooled, the gained mixture at room temperature stirred in the reactor of jam-pack 7 hours.With the reaction mixture concentrating under reduced pressure, residue is dissolved in the ethanol (20ml), adds aqueous ammonium chloride solution (178mg is dissolved in the 10ml water) and 28% ammoniacal liquor (0.44ml), then at room temperature places 12 hours.In reaction mixture, add 4M hydrogenchloride dioxane solution (1ml), then concentrating under reduced pressure, residue preparative HPLC (YMC-Pack ODS YMC, elutriant: 20% acetonitrile solution) refining, the amorphous solid that obtains is dissolved in the methyl alcohol (10ml), add 4M hydrogenchloride dioxane solution (0.5ml), then under reduced pressure be concentrated into dried.In the gained amorphous solid water-soluble (approximately 10ml), after lyophilize, obtain yellow amorphous solid title compound 570mg (yield 70%).
1H?NMR(270MHz，DMSO-d 6)δppm：1.07(3H，t，J＝7.0)，1.83(2H，m)，2.10(2H，m)，2.95-3.25(4H，m)，3.60(2H，m)，4.30(2H，m)，4.69(1H，m)，6.48(1H，dt，J＝16.0，7.0)，6.72(1H，d，J＝16.0)，7.15(2H，d，J＝8.5)，7.56(1H，t，J＝7.5)，7.66(1H，d，J＝7.5)，7.70-8.00(4H，m)；
IR(KBr，cm -1)：1675。
(b) 3-(3-(N-(4-(1-acetimidoyl piperidin-4-yl oxygen) phenyl)-N-ethylamino)-1-(E)-propenyl) benzenyl amidine tri hydrochloride
3-(3-(N-ethyl-N-(4-(piperidin-4-yl oxygen) phenyl) amino)-1-(E)-propenyl) benzenyl amidine tri hydrochloride (420mg) is dissolved in the methyl alcohol (20ml), at room temperature add iminoester hydrochloride (319mg) and triethylamine (0.72ml), then under same temperature, stirred 12 hours.In reaction mixture, add 4M hydrogenchloride dioxane solution (1ml), then concentrating under reduced pressure, residue preparative HPLC (YMC-Pack ODSYMC, elutriant: 20% acetonitrile solution) refining, the gained amorphous solid is dissolved in the methyl alcohol (10ml), add 4M hydrogenchloride dioxane solution (0.5ml), then be evaporated to dried.In the gained amorphous solid water-soluble (approximately 10ml), after lyophilize, obtain colourless amorphous solid title compound 287mg (yield 63%).
1H?NMR(270MHz，DMSO-d 6)δppm：1.09(3H，t，J＝7.0)，1.71(2H，m)，2.03(2H，m)，2.32(3H，s)，3.50-3.95(6H，m)，4.30(2H，m)，4.75(1H，m)，6.49(1H，dt，J＝16.0，6.5)，6.73(1H，d，J＝16.0)，7.00-7.30(2H，m)，7.58(1H，t，J＝7.5)，7.67(1H，d，J＝7.5)，7.75-7.90(4H，m)；
IR(KBr，cm -1)：1673，1623。
Embodiment 25
N-(4-(1-acetimidoyl pyrrolidin-3-yl oxygen) phenyl)-N-(3-(3-carbamimido-phenyl)-2-(E)-propenyl) sulphonamide ethyl acetate dihydrochloride (exemplary compounds number: 90)
(a) N-(3-(3-carbamimido-phenyl)-2-(E)-propenyl)-N-(4-(pyrrolidin-3-yl oxygen) phenyl) sulphonamide ethyl acetate dihydrochloride
N-(4-(1-tertbutyloxycarbonyl pyrrolidin-3-yl oxygen) phenyl)-N-(3-(3-cyano-phenyl)-2-(E)-propenyl) sulphonamide ethyl acetate (2349mg) is dissolved in the mixed solvent of methylene dichloride (60ml) and ethanol (30ml), passed into hydrogenchloride 1 hour under ice-cooled, the gained mixture at room temperature stirred in the reactor of jam-pack 7 hours.With the reaction mixture concentrating under reduced pressure, the gained residue is dissolved in the ethanol (100ml), adds aqueous ammonium chloride solution (440mg is dissolved in the 50ml water) and 28% ammoniacal liquor (0.83ml), then at room temperature places 12 hours.In reaction mixture, add 4M hydrogenchloride dioxane solution (2ml), then concentrating under reduced pressure.Residue preparative HPLC (YMC-Pack ODSYMC, elutriant: 18% acetonitrile solution) refining, the amorphous solid that obtains is dissolved in the methyl alcohol (10ml), adds 4M hydrogenchloride dioxane solution (0.5ml), then under reduced pressure is concentrated into dried.Obtain colourless amorphous solid title compound 272mg (yield 12%).
1H?NMR(270MHz，DMSO-d 6)δppm：1.23(3H，t，J＝7.0)，2.05-2.25(2H，m)，3.15-3.50(4H，m)，4.20(2H，q，J＝7.0)，4.34(2H，s)，4.45(2H，d，J＝5.5)，5.12(1H，m)，6.44(1H，dt，J＝16.0，5.5)，6.56(1H，d，J＝16.0)，7.01(2H，d，J＝9.0)，7.42(2H，d，J＝9.0)，7.54(1H，t，J＝8.0)，7.65-7.75(2H，m)，7.90(1H，s)；
IR(KBr，cm -1)：1737，1675。
(b) N-(4-(1-acetimidoyl pyrrolidin-3-yl oxygen) phenyl)-N-(3-(3-carbamimido-phenyl)-2-(E)-propenyl) sulphonamide ethyl acetate dihydrochloride
N-(3-(3-carbamimido-phenyl)-2-(E)-propenyl)-N-(4-(pyrrolidin-3-yl oxygen) phenyl) sulphonamide ethyl acetate dihydrochloride (400mg) is dissolved in the methyl alcohol (10ml), at room temperature add iminoester hydrochloride (350mg) and triethylamine (0.500ml), then under same temperature, stirred 12 hours.In reaction mixture, add 4M hydrogenchloride dioxane solution (1ml), then concentrating under reduced pressure.(YMC-Pack ODS YMC, elutriant: 20% acetonitrile solution) refining, the gained amorphous solid is dissolved in the methyl alcohol (10ml) residue, adds 4M hydrogenchloride dioxane solution (0.5ml), then is evaporated to dried with preparative HPLC.In the gained amorphous solid water-soluble (approximately 10ml), after lyophilize, obtain colourless amorphous solid title compound 255mg (yield 59%).
1H?NMR(270MHz，DMSO-d 6)δppm：1.23(3H，t，J＝7.0)，2.10-2.30(2H，m)，2.26?and?2.29(total?3H，each?singlet)，3.40-4.05(4H，m)，4.19(2H，q，J＝7.0)，4.34(2H，s)，4.45(2H，d，J＝5.5)，5.10-5.30(1H，m)，6.44(1H，dt，J＝16.0，5.5)，6.56(1H，d，J＝16.0)，7.01?and?7.02(total?2H，each?doublet，J＝9.0)，7.42?and?7.43(total?2H，each?doublet，J＝9.0)，7.54(1H，t，J＝7.5)，7.65-7.75(2H，m)，7.91(1H，s)；
IR(KBr，cm -1)：1738，1672，1629。
Embodiment 26
2-(N-(4-(1-acetimidoyl piperidin-4-yl oxygen) phenyl)-N-(3-(3-carbamimido-phenyl)-2-(E)-propenyl) amino) ethyl propionate tri hydrochloride (exemplary compounds number: 788)
(a) 2-(N-(3-(3-carbamimido-phenyl)-2-(E)-propenyl)-N-(4-(piperidin-4-yl oxygen) phenyl) amino) ethyl propionate tri hydrochloride
2-(N-(4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen) phenyl)-N-(3-(3-cyano-phenyl)-2-(E)-propenyl) amino) ethyl propionate (882mg) is dissolved in the mixed solvent of methylene dichloride (30ml) and ethanol (15ml), passed into hydrogenchloride 1 hour under ice-cooled, the gained mixture at room temperature stirred in the reactor of jam-pack 7 hours.With the reaction mixture concentrating under reduced pressure, the gained residue is dissolved in the ethanol (20ml), adds aqueous ammonium chloride solution (177mg is dissolved in the 10ml water) and 28% ammoniacal liquor (0.43ml), then at room temperature places 12 hours.In reaction mixture, add 4M hydrogenchloride dioxane solution (1mL), then concentrating under reduced pressure.Residue preparative HPLC (YMC-Pack ODSYMC, elutriant: 25% acetonitrile solution) refining, the amorphous solid that obtains is dissolved in the methyl alcohol (10ml), adds 4M hydrogenchloride dioxane solution (0.5ml), then under reduced pressure is concentrated into dried.Obtain the low title compound 200mg (yield is more than 41%) of brown amorphous solid title compound 384mg and purity.
1H?NMR(500MHz，DMSO-d 6)δppm：1.16(3H，t，J＝7.0)，1.44(3H，d，J＝7.0)，1.78(2H，m)，2.04(2H，m)，3.01(2H，m)，3.18(2H，m)，4.09(2H，q，J＝7.0)，3.96-4.15(2H，m)，4.42(1H，m)，4.55(1H，q，J＝7.0)，6.55(1H，dt，J＝16.0，4.5)，6.64(1H，d，J＝16.0)，6.72(2H，d，J＝8.5)，6.86(2H，d，J＝8.5)，7.54(1H，t，J＝8.0)，7.67(1H，d，J＝8.0)，7.73(1H，d，J＝8.0)，7.86(1H，s)；
IR(KBr，cm -1)：1745，1681。
(b) 2-(N-(4-(1-acetimidoyl piperidin-4-yl oxygen) phenyl)-N-(3-(3-carbamimido-phenyl)-2-(E)-propenyl) amino) ethyl propionate tri hydrochloride
The mixture (544mg) that contains 2-(N-(3-(3-carbamimido-phenyl)-2-(E)-propenyl)-N-(4-(piperidin-4-yl oxygen) phenyl) amino) ethyl propionate tri hydrochloride is dissolved in the methyl alcohol (30ml), at room temperature add iminoester hydrochloride (360mg) and triethylamine (0.81ml), then under same temperature, stirred 12 hours.In reaction mixture, add 4M hydrogenchloride dioxane solution (1ml), then concentrating under reduced pressure.(YMC-Pack ODS YMC, elutriant: 25% acetonitrile solution) refining, the gained amorphous solid is dissolved in the methyl alcohol (10ml) residue, adds 4M hydrogenchloride dioxane solution (0.5ml), then is evaporated to dried with preparative HPLC.In the gained amorphous solid water-soluble (approximately 10ml), after lyophilize, obtain light brown amorphous solid title compound 468mg (2 step yield 47%).
1H?NMR(500MHz，DMSO-d 6)δppm：1.15(3H，t，J＝7.0)，1.45(3H，d，J＝7.0)，1.68(2H，m)，1.98(2H，m)，2.29(3H，s)，3.45-3.60(2H，m)，3.65-3.85(2H，m)，4.09(2H，q，J＝7.0)，3.95-4.20(2H，m)，4.49(1H，m)，4.56(1H，q，J＝7.0)，6.56(1H，dt，J＝16.0，4.5)，6.64(1H，d，J＝16.0)，6.76(2H，d，J＝9.0)，6.87(2H，d，J＝9.0)，7.54(1H，t，J＝8.0)，7.70(1H，d，J＝8.0)，7.73(1H，d，J＝8.0)，7.89(1H，s)；
IR(KBr，cm -1)：1745，1673，1623。
Embodiment 27
3-(3-(N-(4-(1-acetimidoyl piperidin-4-yl oxygen) phenyl)-N-methylamino)-1-(E)-propenyl) benzenyl amidine tri hydrochloride (exemplary compounds number: 237)
(a) 3-(3-(N-methyl-N-(4-(piperidin-4-yl oxygen) phenyl) amino)-1-(E)-propenyl) benzenyl amidine tri hydrochloride
3-(3-(N-(4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen) phenyl)-N-methylamino)-1-(E)-propenyl) benzonitrile (761mg) is dissolved in the mixed solvent of methylene dichloride (30ml) and ethanol (15ml), passed into hydrogenchloride 1 hour under ice-cooled, the gained mixture at room temperature stirred in the reactor of jam-pack 7 hours.With the reaction mixture concentrating under reduced pressure, residue is dissolved in the ethanol (20ml), adds aqueous ammonium chloride solution (181mg is dissolved in the 10ml water) and 28% ammoniacal liquor (0.44ml), then at room temperature places 12 hours.In reaction mixture, add 4M hydrogenchloride dioxane solution (1ml), then concentrating under reduced pressure, residue preparative HPLC (YMC-Pack ODS YMC, elutriant: 8% acetonitrile solution) refining, the amorphous solid that obtains is dissolved in the methyl alcohol (10ml), add 4M hydrogenchloride dioxane solution (0.5ml), then under reduced pressure be concentrated into dried.Obtain yellow amorphous solid title compound 401mg (yield 50%).
1H?NMR(270MHz，DMSO-d 6)δppm：1.83(2H，m)，2.08(2H，m)，2.95-3.25(7H，m)，4.22(2H，m)，4.60(1H，m)，6.49(1H，dt，J＝16.0，6.5)，6.71(1H，d，J＝16.0)，6.90-7.90(8H，m)；
IR(KBr，cm -1)：1675。
(b) 3-(3-(N-(4-(1-acetimidoyl piperidin-4-yl oxygen) phenyl)-N-methylamino)-1-(E)-propenyl) benzenyl amidine tri hydrochloride
3-(3-(N-methyl-N-(4-(piperidin-4-yl oxygen) phenyl) amino)-1-(E)-propenyl) benzenyl amidine tri hydrochloride (368mg) is dissolved in the methyl alcohol (20ml), at room temperature add iminoester hydrochloride (290mg) and triethylamine (0.65ml), then under same temperature, stirred 12 hours.In reaction mixture, add 4M hydrogenchloride dioxane solution (1ml), then concentrating under reduced pressure, residue preparative HPLC (YMC-Pack ODSYMC, elutriant: 10% acetonitrile solution) refining, the gained amorphous solid is dissolved in the methyl alcohol (10ml), add 4M hydrogenchloride dioxane solution (0.5ml), then be evaporated to dried.In the gained amorphous solid water-soluble (approximately 10ml), after lyophilize, obtain light brown amorphous solid title compound 288mg (yield 72%).
1H?NMR(270MHz，DMSO-d 6)δppm：1.71(2H，m)，2.02(2H，m)，2.31(3H，s)，3.13(3H，s)，3.40-3.70(4H，m)，4.29(2H，d，J＝7.0)，4.75(1H，m)，6.50(1H，dt，J＝16.0，7.0)，6.76(1H，d，J＝16.0)，7.15(2H，d，J＝9.0)，7.58(1H，t，J＝7.5)，7.69(1H，d，J＝7.5)，7.70-7.85(3H，m)，7.92(1H，s)；
IR(KBr，cm -1)：1672，1625。
Embodiment 28
3-(3-(N-(4-(1-acetimidoyl piperidin-4-yl oxygen) phenyl)-N-(2-hydroxyethyl) amino)-1-(E)-propenyl) benzenyl amidine tri hydrochloride (exemplary compounds number: 478)
(a) 3-(3-(N-(2-hydroxyethyl)-N-(4-(piperidin-4-yl oxygen) phenyl) amino)-1-(E)-propenyl) benzenyl amidine tri hydrochloride
3-(3-(N-(4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen) phenyl)-N-(2-hydroxyethyl) amino)-1-(E)-propenyl) benzonitrile (1098mg) is dissolved in the mixed solvent of methylene dichloride (30ml) and ethanol (15ml), passed into hydrogenchloride 1 hour under ice-cooled, the gained mixture at room temperature stirred in the reactor of jam-pack 6 hours.With the reaction mixture concentrating under reduced pressure, residue is dissolved in the ethanol (20ml), adds aqueous ammonium chloride solution (246mg is dissolved in the 10ml water) and 28% ammoniacal liquor (0.60ml), then at room temperature places 12 hours.In reaction mixture, add 4M hydrogenchloride dioxane solution (1ml), then concentrating under reduced pressure, residue preparative HPLC (YMC-Pack ODSYMC, elutriant: 12% acetonitrile solution) refining, the amorphous solid that obtains is dissolved in the methyl alcohol (10ml), add 4M hydrogenchloride dioxane solution (0.5ml), then under reduced pressure be concentrated into dried.In the gained amorphous solid water-soluble (approximately 10ml), after lyophilize, obtain colourless amorphous solid title compound 555mg (yield 48%).
1H?NMR(500MHz，DMSO-d 6)δppm：1.82(2H，m)，2.07(2H，m)，3.03(2H，m)，3.18(2H，m)，3.54(2H，m)，3.60(2H，m)，4.31(2H，m)，4.62(1H，m)，6.48(1H，dt，J＝16.0，6.5)，6.69(1H，d，J＝16.0)，7.08(2H，m)，7.50(2H，m)，7.58(1H，t，J＝8.0)，7.70(1H，d，J＝8.0)，7.73(1H，d，J＝8.0)，7.86(1H，s)；
IR(KBr，cm -1)：1676。
(b) 3-(3-(N-(4-(1-acetimidoyl piperidin-4-yl oxygen) phenyl)-N-(2-hydroxyethyl) amino)-1-(E)-propenyl) benzenyl amidine tri hydrochloride
3-(3-(N-(2-hydroxyethyl)-N-(4-(piperidin-4-yl oxygen) phenyl) amino)-1-(E)-propenyl) benzenyl amidine tri hydrochloride (295mg) is dissolved in the methyl alcohol (20ml), at room temperature add iminoester hydrochloride (362mg) and triethylamine (0.41ml), then under same temperature, stirred 2 hours.In reaction mixture, add 4M hydrogenchloride dioxane solution (1ml), then concentrating under reduced pressure, residue preparative HPLC (YMC-Pack ODS YMC, elutriant: 16% acetonitrile solution) refining, the gained amorphous solid is dissolved in the methyl alcohol (10ml), add 4M hydrogenchloride dioxane solution (0.5ml), then be evaporated to dried.In the gained amorphous solid water-soluble (approximately 10ml), after lyophilize, obtain faint yellow amorphous solid title compound 175mg (yield 55%).
1H?NMR(500MHz，DMSO-d 6)δppm：1.71(2H，m)，2.03(2H，m)，2.31(3H，s)，3.40-4.00(8H，m)，4.32(2H，m)，4.67(1H，m)，6.50(1H，dt，J＝16.0，6.5)，6.70(1H，d，J＝16.0)，7.08(2H，m)，7.50(2H，m)，7.58(1H，t，J＝8.0)，7.70(1H，d，J＝8.0)，7.75(1H，d，J＝8.0)，7.89(1H，s)；
IR(KBr，cm -1)：1673，1626。
Embodiment 29
N-(4-(1-acetimidoyl piperidin-4-yl oxygen)-3-carbethoxy phenyl)-N-(3-(3-carbamimido-phenyl)-2-(E)-propenyl) sulphonamide ethyl acetate dihydrochloride (exemplary compounds number: 1450)
(a) N-(3-(3-carbamimido-phenyl)-2-(E)-propenyl)-N-(3-ethoxycarbonyl-4-(piperidin-4-yl oxygen) phenyl) sulphonamide ethyl acetate dihydrochloride
N-(4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-3-carbethoxy phenyl)-N-(3-(3-cyano-phenyl)-2-(E)-propenyl) sulphonamide ethyl acetate (2.45g) is dissolved in the mixed solvent of methylene dichloride (25ml) and ethanol (25ml), passed into hydrogenchloride 1.5 hours under ice-cooled, the gained mixture at room temperature stirred in the reactor of jam-pack 4.5 hours.With the reaction mixture concentrating under reduced pressure, the gained residue is dissolved in the ethanol (20ml), add aqueous ammonium chloride solution (0.44g is dissolved in the 5ml water) and 28% ammoniacal liquor (1.00ml), reaction mixture at room temperature stirred 0.5 hour, then placed 13 hours.With the reaction mixture concentrating under reduced pressure, residue HPLC (YMC-Pack ODS YMC, elutriant: 22% acetonitrile solution) refining, the gained amorphous solid is dissolved in the ethanol (20ml), add 4M hydrogenchloride ethyl acetate solution (1.90ml), then under reduced pressure be concentrated into dried.Obtain colourless amorphous solid title compound 1.41g (yield 58%).
1H?NMR(500MHz，DMSO-d 6)δppm：1.23(3H，t，J＝7.0)，1.29(3H，t，J＝7.0)，1.85-1.95(2H，m)，2.05-2.15(2H，m)，3.05-3.40(4H，m)，4.19(2H，q，J＝7.0)，4.28(2H，q，J＝7.0)，4.41(2H，s)，4.47(2H，d，J＝6.0)，4.86(1H，m)，6.45(1H，dt，J＝16.0，6.0)，6.57(1H，d，J＝16.0)，7.30(1H，m)，7.55(1H，m)，7.61(1H，m)，7.65-7.80(3H，m)，7.89(1H，m)；
IR(KBr，cm -1)：1729，1676。
(b) N-(4-(1-acetimidoyl piperidin-4-yl oxygen)-3-carbethoxy phenyl)-N-(3-(3-carbamimido-phenyl)-2-(E)-propenyl) sulphonamide ethyl acetate dihydrochloride
N-(3-(3-carbamimido-phenyl)-2-(E)-propenyl)-N-(3-ethoxycarbonyl-4-(piperidin-4-yl oxygen) phenyl) sulphonamide ethyl acetate dihydrochloride (1.24g) is dissolved in the ethanol (20ml), at ice-cooled lower adding iminoester hydrochloride (0.72g) and triethylamine (1.70ml), at room temperature stir after 1.5 hours and placed 15 hours.With the reaction mixture concentrating under reduced pressure, residue preparative HPLC (YMC-Pack ODS YMC, elutriant: 22% acetonitrile solution) refining, the gained amorphous solid is dissolved in the ethanol (10ml), add 4M hydrogenchloride ethyl acetate solution (1.30ml), then under reduced pressure be concentrated into dried.Obtain colourless amorphous solid title compound 1.01g (yield 76%).
1H?NMR(500MHz，DMSO-d 6)δppm：1.23(3H，t，J＝7.0)，1.27(3H，t，J＝7.0)，1.75-1.90(2H，m)，1.95-2.10(2H，m)，2.31(3H，s)，3.60-3.70(3H，m)，3.70-3.80(1H，m)，4.19(2H，q，J＝7.0)，4.26(2H，q，J＝7.0)，4.41(2H，s)，4.47(2H，d，J＝6.0)，4.90(1H，m)，6.45(1H，dt，J＝16.0，6.0)，6.58(1H，d，J＝16.0)，7.32(1H，m)，7.55(1H，m)，7.62(1H，m)，7.65-7.70(3H，m)，7.90(1H，m)；
IR(KBr，cm -1)：1730，1673，1624。
Embodiment 30
N-(4-(1-acetimidoyl piperidin-4-yl oxygen)-3-carboxyl phenyl)-N-(3-(3-carbamimido-phenyl)-2-(E)-propenyl) sulphonamide acetic acid dihydrochloride (exemplary compounds number: 1975)
N-(4-(1-acetimidoyl piperidin-4-yl oxygen)-3-carbethoxy phenyl)-N-(3-(3-carbamimido-phenyl)-2-(E)-propenyl) sulphonamide ethyl acetate dihydrochloride (0.30g) is dissolved in the 3M hydrochloric acid (6ml), stirs 2 hours at 80 ℃.Reaction mixture carries out concentrating under reduced pressure after being cooled to room temperature, residue preparative HPLC (YMC-Pack ODS YMC, elutriant: 10% acetonitrile solution) refining, the gained amorphous solid is dissolved in the 1M hydrochloric acid (1.10ml), then under reduced pressure is concentrated into dried.Obtain colourless amorphous solid title compound 0.22g (yield 79%).
1H?NMR(500MHz，DMSO-d 6)δppm：1.75-1.90(2H，m)，1.90-2.10(2H，m)，2.29(3H，s)，3.55-3.75(4H，m)，4.26(2H，s)，4.47(2H，d，J＝6.0)，4.87(1H，m)，6.44(1H，dt，J＝16.0，6.0)，6.57(1H，d，J＝16.0)，7.28(1H，m)，7.50-7，65(2H，m)，7.65-7.80(3H，m)，7.86(1H，m)；
IR(KBr，cm -1)：1726，1673，1627。
Embodiment 31
N-(4-(1-acetimidoyl piperidin-4-yl oxygen)-3-bromophenyl)-N-(3-(3-carbamimido-phenyl)-2-(E)-propenyl) sulphonamide ethyl acetate dihydrochloride (exemplary compounds number: 1416)
(a) N-(3-(3-carbamimido-phenyl)-2-(E)-propenyl)-N-(3-bromo-4-(piperidin-4-yl oxygen) phenyl) sulphonamide ethyl acetate dihydrochloride
N-(3-bromo-4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen) phenyl)-N-(3-(3-cyano-phenyl)-2-(E)-propenyl) sulphonamide ethyl acetate (2.20g) is dissolved in the mixed solvent of methylene dichloride (25ml) and ethanol (25ml), passed into hydrogenchloride 1.5 hours under ice-cooled, the gained mixture at room temperature stirred in the reactor of jam-pack 5 hours.With the reaction mixture concentrating under reduced pressure, the gained residue is dissolved in the ethanol (20ml), add aqueous ammonium chloride solution (0.40g is dissolved in the 5ml water) and 28% ammoniacal liquor (0.90ml), reaction mixture at room temperature stirred 0.5 hour, then placed 15 hours.With the reaction mixture concentrating under reduced pressure, residue HPLC (YMC-Pack ODS YMC, elutriant: 22% acetonitrile solution) refining, the gained amorphous solid is dissolved in the ethanol (20ml), add 4M hydrogenchloride ethyl acetate solution (1.70ml), then under reduced pressure be concentrated into dried.Obtain colourless amorphous solid title compound 1.34g (yield 61%).
1H?NMR(500MHz，DMSO-d 6)δppm：1.23(3H，t，J＝7.0)，1.85-1.95(2H，m)，2.05-2.15(2H，m)，3.05-3.20(4H，m)，4.20(2H，q，J＝7.0)，4.42(2H，s)，4.47(2H，d，J＝6.0)，4.80(1H，m)，6.44(1H，dt，J＝16.0，6.0)，6.58(1H，d，J＝16.0)，7.27(1H，m)，7.45(1H，m)，7.55(1H，m)，7.65-7.80(3H，m)，7.90(1H，m)；
IR(KBr，cm -1)：1737，1675。
(b) N-(4-(1-acetimidoyl piperidin-4-yl oxygen)-3-bromophenyl)-N-(3-(3-carbamimido-phenyl)-2-(E)-propenyl) sulphonamide ethyl acetate dihydrochloride
N-(3-(3-carbamimido-phenyl)-2-(E)-propenyl)-N-(3-bromo-4-(piperidin-4-yl oxygen) phenyl) sulphonamide ethyl acetate dihydrochloride (1.17g) is dissolved in the ethanol (30ml), at ice-cooled lower adding iminoester hydrochloride (0.67g) and triethylamine (1.50ml), at room temperature stir after 2 hours and placed 14 hours.With the reaction mixture concentrating under reduced pressure, residue preparative HPLC (YMC-Pack ODS YMC, elutriant: 22% acetonitrile solution) refining, the gained amorphous solid is dissolved in the ethanol (10ml), add 4M hydrogenchloride ethyl acetate solution (1.20ml), then under reduced pressure be concentrated into dried.Obtain colourless amorphous solid title compound 0.97g (yield 77%).
1H?NMR(500MHz，DMSO-d 6)δppm：1.23(3H，t，J＝7.0)，1.70-1.90(2H，m)，1.95-2.15(2H，m)，2.30(3H，s)，3.55-3.75(4H，m)，4.19(2H，q，J＝7.0)，4.42(2H，s)，4.47(2H，d，J＝6.0)，4.85(1H，m)，6.44(1H，dt，J＝16.0，6.0)，6.58(1H，d，J＝16.0)，7.29(1H，m)，7.45(1H，m)，7.55(1H，m)，7.65-7.80(3H，m)，7.90(1H，m)；
IR(KBr，cm -1)：1738，1674，1625。
Embodiment 32
N-(4-(1-acetimidoyl piperidin-4-yl oxygen)-3-bromophenyl)-N-(3-(3-carbamimido-phenyl)-2-(E)-propenyl) sulphonamide acetic acid dihydrochloride (exemplary compounds number: 1945)
N-(4-(1-acetimidoyl piperidin-4-yl oxygen)-3-bromophenyl)-N-(3-(3-carbamimido-phenyl)-2-(E)-propenyl) sulphonamide ethyl acetate dihydrochloride (0.80g) is dissolved in the 3M hydrochloric acid (15ml), stirs 2 hours at 90 ℃.Reaction mixture carries out concentrating under reduced pressure after being cooled to room temperature, residue preparative HPLC (YMC-PackODS YMC, elutriant: 22% acetonitrile solution) refining, the gained amorphous solid is dissolved in the ethanol (15ml), add 4M hydrogenchloride ethyl acetate solution (0.5ml), then under reduced pressure be concentrated into dried.Obtain colourless amorphous solid title compound 0.37g (yield 48%).
1H?NMR(500MHz，DMSO-d 6)δppm：1.70-1.85(2H，m)，1.95-2.10(2H，m)，2.30(3H，s)，3.55-3.75(4H，m)，4.26(2H，s)，4.47(2H，d，J＝6.0)，4.85(1H，m)，6.45(1H，dt，J＝16.0，6.0)，6.58(1H，d，J＝16.0)，7.29(1H，m)，7.46(1H，m)，7.55(1H，m)，7.65-7.75(3H，m)，7.89(1H，m)；
IR(KBr，cm -1)：1732，1672，1626.
Embodiment 33
N-(4-(1-acetimidoyl piperidin-4-yl oxygen)-3-isopropyl phenyl)-N-(3-(3-carbamimido-phenyl)-2-(E)-propenyl) sulphonamide ethyl acetate dihydrochloride (exemplary compounds number: 1426)
(a) N-(3-(3-carbamimido-phenyl)-2-(E)-propenyl)-N-(3-sec.-propyl-4-(piperidin-4-yl oxygen) phenyl) sulphonamide ethyl acetate dihydrochloride
N-(4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-3-isopropyl phenyl)-N-(3-(3-cyano-phenyl)-2-(E)-propenyl) sulphonamide ethyl acetate (1.82g) is dissolved in the mixed solvent of methylene dichloride (30ml) and ethanol (30ml), passed into hydrogenchloride 1.5 hours under ice-cooled, the gained mixture at room temperature stirred in the reactor of jam-pack 2 hours.With the reaction mixture concentrating under reduced pressure, the gained residue is dissolved in the ethanol (20ml), add aqueous ammonium chloride solution (0.35g is dissolved in the 5ml water) and 28% ammoniacal liquor (0.80ml), reaction mixture at room temperature stirred 0.5 hour, then placed 13 hours.With the reaction mixture concentrating under reduced pressure, residue HPLC (YMC-Pack ODS YMC, elutriant: 25% acetonitrile solution) refining, the gained amorphous solid is dissolved in the ethanol (20ml), add 4M hydrogenchloride ethyl acetate solution (1.40ml), then under reduced pressure be concentrated into dried.Obtain colourless amorphous solid title compound 0.92g (yield 51%).
1H?NMR(500MHz，DMSO-d 6)δppm：1.15(6H，d，J＝7.0)，1.24(3H，t，J＝7.0)，1.80-1.95(2H，m)，2.05-2.20(2H，m)，3.00-3.20(4H，m)，3.21(1H，m)，4.21(2H，q，J＝7.0)，4.33(2H，s)，4.43(2H，d，J＝6.0)，4.68(1H，m)，6.45(1H，dt，J＝16.0，6.0)，6.55(1H，d，J＝16.0)，7.04(1H，d，J＝9.0)，7.23(1H，dd，J＝9.0，3.0)，7.29(1H，d，J＝3.0)，7.54(1H，m)，7.65-7.75(2H，m)，7.89(1H，m)；
IR(KBr，cm -1)：1738，1676。
(b) N-(4-(1-acetimidoyl piperidin-4-yl oxygen)-3-isopropyl phenyl)-N-(3-(3-carbamimido-phenyl)-2-(E)-propenyl) sulphonamide ethyl acetate dihydrochloride
N-(3-(3-carbamimido-phenyl)-2-(E)-propenyl)-N-(3-sec.-propyl-4-(piperidin-4-yl oxygen) phenyl) sulphonamide ethyl acetate dihydrochloride (0.78g) is dissolved in the ethanol (30ml), at ice-cooled lower adding iminoester hydrochloride (0.50g) and triethylamine (1.10ml), at room temperature stir after 7 hours and placed 12 hours.With the reaction mixture concentrating under reduced pressure, residue preparative HPLC (YMC-Pack ODS YMC, elutriant: 25% acetonitrile solution) refining, the gained amorphous solid is dissolved in the ethanol (20ml), add 4M hydrogenchloride ethyl acetate solution (0.90ml), then under reduced pressure be concentrated into dried.Obtain colourless amorphous solid title compound 0.67g (yield 80%).
1H?NMR(500MHz，DMSO-d 6)δppm：1.14(6H，d，J＝7.0)，1.24(3H，t，J＝7.0)，1.70-1.85(2H，m)，1.95-2.10(2H，m)，2.30(3H，s)，3.22(1H，m)，3.50-3.60(1H，m)，3.60-3.70(2H，m)，3.70-3.80(1H，m)，4.21(2H，q，J＝7.0)，4.33(2H，s)，4.43(2H，d，J＝6.0)，4.74(1H，m)，6.45(1H，dt，J＝16.0，6.0)，6.55(1H，d，J＝16.0)，7.07(1H，d，J＝9.0)，7.23(1H，dd，J＝9.0，3.0)，7.28(1H，d，J＝3.0)，7.55(1H，m)，7.71(2H，m)，7.90(1H，m)；
IR(KBr，cm -1)：1739，1673，1623。
Embodiment 34
N-(4-(1-acetimidoyl piperidin-4-yl oxygen)-3-isopropyl phenyl)-N-(3-(3-carbamimido-phenyl)-2-(E)-propenyl) sulphonamide acetic acid dihydrochloride (exemplary compounds number: 1955)
N-(4-(1-acetimidoyl piperidin-4-yl oxygen)-3-isopropyl phenyl)-N-(3-(3-carbamimido-phenyl)-2-(E)-propenyl) sulphonamide ethyl acetate dihydrochloride (0.51g) is dissolved in the 3M hydrochloric acid (20ml), stirs 2 hours at 90 ℃.Reaction mixture carries out concentrating under reduced pressure after being cooled to room temperature, residue preparative HPLC (YMC-Pack ODS YMC, elutriant: 25% acetonitrile solution) refining, the gained amorphous solid is dissolved in the 1M hydrochloric acid (1.70ml), then under reduced pressure be concentrated into driedly, obtain colourless amorphous solid title compound 0.33g (yield 66%).
1H?NMR(500MHz，DMSO-d 6)δppm：1.14(6H，d，J＝7.0)，1.70-1.85(2H，m)，1.95-2.10(2H，m)，2.30(3H，s)，3.21(1H，m)，3.50-3.60(1H，m)，3.60-3.70(2H，m)，3.70-3.80(1H，m)，4.21(2H，s)，4.44(2H，d，J＝6.0)，4.73(1H，m)，6.46(1H，dt，J＝16.0，6.0)，6.54(1H，d，J＝16.0)，7.06(1H，d，J＝9.0)，7.24(1H，dd，J＝9.0，3.0)，7.29(1H，d，J＝3.0)，7.54(1H，m)，7.71(2H，m)，7.90(1H，m)；
IR(KBr，cm -1)：1733，1673，1625。
Embodiment 35
N-(4-(1-acetimidoyl piperidin-4-yl oxygen)-3-formamyl phenyl)-N-(3-(3-carbamimido-phenyl)-2-(E)-propenyl) sulphonamide ethyl acetate dihydrochloride (exemplary compounds number: 1460)
(a) N-(3-(3-carbamimido-phenyl)-2-(E)-propenyl)-N-(3-formamyl-4-(piperidin-4-yl oxygen) phenyl) sulphonamide ethyl acetate dihydrochloride
N-(4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-3-formamyl phenyl)-N-(3-(3-cyano-phenyl)-2-(E)-propenyl) sulphonamide ethyl acetate (2.40g) is dissolved in the mixed solvent of methylene dichloride (20ml) and ethanol (20ml); passed into hydrogenchloride 2.5 hours under ice-cooled, the gained mixture at room temperature stirred in the reactor of jam-pack 6 hours.With the reaction mixture concentrating under reduced pressure, the gained residue is dissolved in the ethanol (20ml), add aqueous ammonium chloride solution (0.50g is dissolved in the 5ml water) and 28% ammoniacal liquor (1.10ml), reaction mixture at room temperature stirred 0.5 hour, then placed 13 hours.With the reaction mixture concentrating under reduced pressure, residue HPLC (YMC-Pack ODS YMC, elutriant: 15% acetonitrile solution) refining, the gained amorphous solid is dissolved in the ethanol (20ml), add 4M hydrogenchloride ethyl acetate solution (0.90ml), then under reduced pressure be concentrated into dried.Obtain colourless amorphous solid title compound 0.60g (yield 25%).
1H?NMR(500MHz，DMSO-d 6)δppm：1.23(3H，t，J＝7.0)，1.85-2.00(2H，m)，2.05-2.20(2H，m)，3.00-3.10(2H，m)，3.15-3.25(2H，m)，4.20(2H，q，J＝7.0)，4.38(2H，s)，4.47(2H，d，J＝6.0)，4.80(1H，m)，6.45(1H，dt，J＝16.0，6.0)，6.57(1H，d，J＝16.0)，7.24(1H，m)，7.50(1H，m)，7.54(1H，m)，7.65-7.75(3H，m)，7.90(1H，m)；
IR(KBr，cm -1)：1736，1671，1658。
(b) N-(4-(1-acetimidoyl piperidin-4-yl oxygen)-3-formamyl phenyl)-N-(3-(3-carbamimido-phenyl)-2-(E)-propenyl) sulphonamide ethyl acetate dihydrochloride
N-(3-(3-carbamimido-phenyl)-2-(E)-propenyl)-N-(3-formamyl-4-(piperidin-4-yl oxygen) phenyl) sulphonamide ethyl acetate dihydrochloride (1.24g) is dissolved in the ethanol (20ml); at ice-cooled lower adding iminoester hydrochloride (0.27g) and triethylamine (0.60ml), at room temperature stir after 0.5 hour and placed 14 hours.With the reaction mixture concentrating under reduced pressure, residue preparative HPLC (YMC-Pack ODSYMC, elutriant: 15% acetonitrile solution) refining, the gained amorphous solid is dissolved in the ethanol (10ml), add 4M hydrogenchloride ethyl acetate solution (0.50ml), then under reduced pressure be concentrated into dried.Obtain colourless amorphous solid title compound 0.37g (yield 78%).
1H?NMR(400MHz，DMSO-d 6)δppm：1.24(3H，t，J＝7.0)，1.80-1.95(2H，m)，2.00-2.15(2H，m)，2.29(3H，s)，3.45-3.65(2H，m)，3.65-3.85(2H，m)，4.20(2H，q，J＝7.0)，4.37(2H，s)，4.47(2H，d，J＝6.0)，4.86(1H，m)，6.44(1H，dt，J＝16.0，6.0)，6.58(1H，d，J＝16.0)，7.28(1H，m)，7.45-7.60(2H，m)，7.70(2H，m)，7.78(1H，m)，7.88(1H，m)；
IR(KBr，cm -1)：1737，1672。
Embodiment 36
N-(4-(1-acetimidoyl piperidin-4-yl oxygen)-3-formamyl phenyl)-N-(3-(3-carbamimido-phenyl)-2-(E)-propenyl) sulphonamide acetic acid dihydrochloride (exemplary compounds number: 1989)
N-(4-(1-acetimidoyl piperidin-4-yl oxygen)-3-formamyl phenyl)-N-(3-(3-carbamimido-phenyl)-2-(E)-propenyl) sulphonamide ethyl acetate dihydrochloride (0.20g) is dissolved in the 1.5M hydrochloric acid (20ml), stirs 6 hours at 60 ℃.Reaction mixture carries out concentrating under reduced pressure after being cooled to room temperature, residue preparative HPLC (YMC-Pack ODS YMC, elutriant: 15% acetonitrile solution) refining, the gained amorphous solid is dissolved in the 1M hydrochloric acid (0.75ml), then under reduced pressure be concentrated into driedly, obtain colourless amorphous solid title compound 0.14g (yield 71%).
1H?NMR(500MHz，DMSO-d 6)δppm：1.75-1.95(2H，m)，2.00-2.15(2H，m)，2.29(3H，s)，3.45-3.65(2H，m)，3.65-3.85(2H，m)，4.24(2H，s)，4.47(2H，d，J＝6.0)，4.85(1H，m)，6.45(1H，dt，J＝16.0，6.0)，6.57(1H，d，J＝16.0)，7.27(1H，m)，7.45-7.60(2H，m)，7.70(2H，m)，7.77(1H，m)，7.88(1H，m)；
IR(KBr，cm -1)：1729，1672。
Embodiment 37
N-(4-(1-acetimidoyl piperidin-4-yl oxygen)-3-(N '-methylamino formyl radical) phenyl)-N-(3-(3-carbamimido-phenyl)-2-(E)-propenyl) sulphonamide ethyl acetate dihydrochloride (exemplary compounds number: 1462)
(a) N-(3-(3-carbamimido-phenyl)-2-(E)-propenyl)-N-(3-(N '-methylamino formyl radical)-4-(piperidin-4-yl oxygen) phenyl) sulphonamide ethyl acetate dihydrochloride
N-(4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-3-(N ' methylamino formyl radical) phenyl)-N-(3-(3-cyano-phenyl)-2-(E)-propenyl) sulphonamide ethyl acetate (1.50g) is dissolved in the mixed solvent of methylene dichloride (20ml) and ethanol (20ml); passed into hydrogenchloride 1.5 hours under ice-cooled, the gained mixture at room temperature stirred in the reactor of jam-pack 3.5 hours.With the reaction mixture concentrating under reduced pressure, the gained residue is dissolved in the ethanol (20ml), adds aqueous ammonium chloride solution (0.29g is dissolved in the 5ml water) and 28% ammoniacal liquor (0.66ml), at room temperature stirs 2 hours, then places 15 hours.With the reaction mixture concentrating under reduced pressure, residue HPLC (YMC-Pack ODS YMC, elutriant: 15% acetonitrile solution) refining, the gained amorphous solid is dissolved in the ethanol (20ml), add 4M hydrogenchloride ethyl acetate solution (1.55ml), then under reduced pressure be concentrated into dried.Obtain colourless amorphous solid title compound 1.14g (yield 73%).
1H?NMR(400MHz，DMSO-d 6)δppm：1.23(3H，t，J＝7.0)，1.85-1.95(2H，m)，2.05-2.15(2H，m)，2.79(3H，m)，2.95-3.10(2H，m)，3.10-3.25(2H，m)，4.20(2H，q，J＝7.0)，4.38(2H，s)，4.47(2H，d，J＝6.0)，4.79(1H，m)，6.45(1H，dt，J＝16.0，6.0)，6.58(1H，d，J＝16.0)，7.24(1H，m)，7.48(1H，m)，7.54(1H，m)，7.62(1H，m)，7.12(2H，m)，7.92(1H，m)；
IR(KBr，cm -1)：1737，1676，1641。
(b) N-(4-(1-acetimidoyl piperidin-4-yl oxygen)-3-(N ' methylamino formyl radical) phenyl)-N-(3-(3-carbamimido-phenyl)-2-(E)-propenyl) sulphonamide ethyl acetate dihydrochloride
N-(3-(3-carbamimido-phenyl)-2-(E)-propenyl)-N-(3-(N '-methylamino formyl radical)-4-(piperidin-4-yl oxygen) phenyl) sulphonamide ethyl acetate dihydrochloride (1.00g) is dissolved in the ethanol (30ml); at ice-cooled lower adding iminoester hydrochloride (0.60g) and triethylamine (1.3ml), at room temperature stirred 8 hours.With the reaction mixture concentrating under reduced pressure, residue preparative HPLC (YMC-Pack ODS YMC, elutriant: 15% acetonitrile solution) refining, the gained amorphous solid is dissolved in the ethanol (10ml), add 4M hydrogenchloride ethyl acetate solution (1.00ml), then under reduced pressure be concentrated into dried.Obtain colourless amorphous solid title compound 0.79g (yield 74%).
1H?NMR(400MHz，DMSO-d 6)δppm：1.23(3H，t，J＝7.0)，1.75-1.90(2H，m)，1.95-2.10(2H，m)，2.30(3H，s)，2.78(3H，s)，3.50-3.80(4H，m)，4.20(2H，q，J＝7.0)，4.37(2H，s)，4.47(2H，d，J＝6.0)，4.84(1H，m)，6.44(1H，dt，J＝16.0，6.0)，6.58(1H，d，J＝16.0)，7.27(1H，m)，7.50(1H，m)，7.55(1H，m)，7.65-7.75(3H，m)，7.90(1H，m)；
IR(KBr，cm -1)：1738，1673，1633。
Embodiment 38
N-(4-(1-acetimidoyl piperidin-4-yl oxygen)-3-(N ' methylamino formyl radical) phenyl)-N-(3-(3-carbamimido-phenyl)-2-(E)-propenyl) sulphonamide acetic acid dihydrochloride (exemplary compounds number: 1991)
N-(4-(1-acetimidoyl piperidin-4-yl oxygen)-3-(N '-methylamino formyl radical) phenyl)-N-(3-(3-carbamimido-phenyl)-2-(E)-propenyl) sulphonamide ethyl acetate dihydrochloride (0.53g) is dissolved in the 1.5M hydrochloric acid (30ml), stirred 8 hours at 60 ℃.Reaction mixture carries out concentrating under reduced pressure after being cooled to room temperature, residue preparative HPLC (YMC-Pack ODS YMC, elutriant: 15% acetonitrile solution) refining, the gained amorphous solid is dissolved in the 1M hydrochloric acid (2.20ml), then under reduced pressure is concentrated into dried.Obtain colourless amorphous solid title compound 0.42g (yield 82%).
1H?NMR(400MHz，DMSO-d 6)δppm：1.75-1.90(2H，m)，1.95-2.10(2H，m)，2.30(3H，s)，2.78(3H，s)，3.50-3.85(4H，m)，4.25(2H，s)，4.47(2H，d，J＝6.0)，4.84(1H，m)，6.45(1H，dt，J＝16.0，6.0)，6.57(1H，d，J＝16.0)，7.27(1H，m)，7.45-7.60(2H，m)，7.65-7.75(3H，m)，7.90(1H，m)；
IR(KBr，cm -1)：1732，1673，1628。
Embodiment 39
N-(4-(1-acetimidoyl piperidin-4-yl oxygen)-3-(N ', N '-formyl-dimethylamino) phenyl)-N-(3-(3-carbamimido-phenyl)-2-(E)-propenyl) sulphonamide ethyl acetate dihydrochloride (exemplary compounds number: 1466)
(a) N-(3-(3-carbamimido-phenyl)-2-(E)-propenyl)-N-(3-(N ', N '-formyl-dimethylamino)-4-(piperidin-4-yl oxygen) phenyl) sulphonamide ethyl acetate dihydrochloride
N-(4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-3-(N '; N ' formyl-dimethylamino) phenyl)-N-(3-(3-cyano-phenyl)-2-(E)-propenyl) sulphonamide ethyl acetate (1.70g) is dissolved in the mixed solvent of methylene dichloride (20ml) and ethanol (20ml); passed into hydrogenchloride 1.5 hours under ice-cooled, the gained mixture at room temperature stirred in the reactor of jam-pack 3.5 hours.With the reaction mixture concentrating under reduced pressure, the gained residue is dissolved in the ethanol (20ml), adds aqueous ammonium chloride solution (0.30g is dissolved in the 5ml water) and 28% ammoniacal liquor (0.70ml), at room temperature stirs 5 hours, then places 13 hours.With the reaction mixture concentrating under reduced pressure, residue HPLC (YMC-Pack ODS YMC, elutriant: 15% acetonitrile solution) refining, the gained amorphous solid is dissolved in the ethanol (20ml), add 4M hydrogenchloride ethyl acetate solution (1.00ml), then under reduced pressure be concentrated into dried.Obtain colourless amorphous solid title compound 0.75g (yield 44%).
1H?NMR(400MHz，DMSO-d 6)δppm：1.22(3H，t，J＝7.0)，1.75-1.95(2H，m)，1.95-2.15(2H，m)，2.69(3H，s)，2.97(3H，s)，2.95-3.15(4H，m)，4.19(2H，q，J＝7.0)，4.38(2H，s)，4.35-4.55(2H，m)，4.75(1H，m)，6.43(1H，dt，J＝16.0，6.0)，6.55(1H，d，J＝16.0)，7.22(1H，d，J＝9.0)，7.30(1H，d，J＝3.0)，7.45(1H，dd，J＝9.0，3.0)，7.54(1H，t，J＝8.0)，7.70(2H，d，J＝8.0)，7.88(1H，s)；
IR(KBr，cm -1)：1738，1676，1618。
(b) N-(4-(1-acetimidoyl piperidin-4-yl oxygen)-3-(N ', N '-formyl-dimethylamino) phenyl)-N-(3-(3-carbamimido-phenyl)-2-(E)-propenyl) sulphonamide ethyl acetate dihydrochloride
N-(3-(3-carbamimido-phenyl)-2-(E)-propenyl)-N-(3-(N '; N '-formyl-dimethylamino)-and 4-(piperidin-4-yl oxygen) phenyl) sulphonamide ethyl acetate dihydrochloride (0.60g) is dissolved in the ethanol (20ml); at ice-cooled lower adding iminoester hydrochloride (0.35g) and triethylamine (0.80ml), at room temperature stir after 0.5 hour and placed 12 hours.With the reaction mixture concentrating under reduced pressure, residue preparative HPLC (YMC-Pack ODS YMC, elutriant: 20% acetonitrile solution) refining, the gained amorphous solid is dissolved in the ethanol (20ml), add 4M hydrogenchloride ethyl acetate solution (0.60ml), then under reduced pressure be concentrated into dried.Obtain colourless amorphous solid title compound 0.47g (yield 73%).
1H?NMR(400MHz，DMSO-d 6)δppm：1.22(3H，t，J＝7.0)，1.60-1.85(2H，m)，1.85-2.10(2H，m)，2.29(3H，s)，2.69(3H，s)，2.95(3H，s)，3.50-3.70(4H，m)，4.19(2H，q，J＝7.0)，4.35-4.55(2H，m)，4.39(2H，s)，4.79(1H，m)，6.44(1H，dt，J＝16.0，6.0)，6.55(1H，d，J＝16.0)，7.25(1H，d，J＝9.0)，7.29(1H，d，J＝3.0)，7.45(1H，dd，J＝9.0，3.0)，7.54(1H，m)，7.65-7.75(2H，m)，7.90(1H，s)；
IR(KBr，cm -1)：1738，1673，1618。
Embodiment 40
N-(4-(1-acetimidoyl piperidin-4-yl oxygen)-3-(N ', N '-formyl-dimethylamino) phenyl)-N-(3-(3-carbamimido-phenyl)-2-(E)-propenyl) sulphonamide acetic acid dihydrochloride (exemplary compounds number: 1995)
N-(4-(1-acetimidoyl piperidin-4-yl oxygen)-3-(N '; N ' formyl-dimethylamino) phenyl)-and N-(3-(3-carbamimido-phenyl)-2-(E)-propenyl) sulphonamide ethyl acetate dihydrochloride (440mg) is dissolved in the 1.5M hydrochloric acid (10ml), stirred 9.5 hours at 60 ℃.Reaction mixture carries out concentrating under reduced pressure after being cooled to room temperature, residue preparative HPLC (YMC-Pack ODS YMC, elutriant: 10% acetonitrile solution) refining, the gained amorphous solid is dissolved in the 1M hydrochloric acid (1.20ml), then under reduced pressure be concentrated into driedly, obtain colourless amorphous solid title compound 0.24g (yield 83%).
1H?NMR(400MHz，DMSO-d 6)δppm：1.65-1.85(2H，m)，1.90-2.10(2H，m)，2.28(3H，s)，2.69(3H，s)，2.95(3H，s)，3.50-3.70(4H，m)，4.25(2H，s)，4.35-4.55(2H，m)，4.78(1H，m)，6.43(1H，dt，J＝16.0，6.0)，6.55(1H，d，J＝16.0)，7.24(1H，d，J＝9.0)，7.29(1H，d，J＝3.0)，7.46(1H，dd，J＝9.0，3.0)，7.54(1H，m)，7.65-7.75(2H，m)，7.88(1H，s)；
IR(KBr，cm -1)：1733，1672，1614。
Embodiment 41
N-(4-(1-acetimidoyl piperidin-4-yl oxygen)-3-chloro-phenyl-)-N-(3-(5-amidino groups-2-hydroxy phenyl)-2-(E)-propenyl) sulphonamide ethyl acetate dihydrochloride (exemplary compounds number: 1843)
(a) N-(3-(5-amidino groups-2-hydroxy phenyl)-2-(E)-propenyl)-N-(3-chloro-4-(piperidin-4-yl oxygen) phenyl) sulphonamide ethyl acetate
N-(4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-3-chloro-phenyl-)-N-(3-(5-cyano group-2-methoxyl group methoxy phenyl)-2-(E)-propenyl) sulphonamide ethyl acetate (1.40g) is dissolved in the mixed solvent of methylene dichloride (20ml) and ethanol (20ml), passed into hydrogenchloride 1.5 hours under ice-cooled, the gained mixture at room temperature stirred in the reactor of jam-pack 2 hours.With the reaction mixture concentrating under reduced pressure, the gained residue is dissolved in the ethanol (40ml), adds aqueous ammonium chloride solution (0.2g is dissolved in the 10ml water) and 28% ammoniacal liquor (0.5ml), at room temperature stirs 0.5 hour, then places 12 hours.With the reaction mixture concentrating under reduced pressure, and residue HPLC (YMC-Pack ODS YMC, elutriant: 15% acetonitrile solution) refining, then under reduced pressure be concentrated into dried.Obtain colourless amorphous solid title compound 0.1g (yield 4%).
1H?NMR(500MHz，DMSO-d 6)δppm：1.23(3H，t，J＝7.0)，1.85-1.95(2H，m)，2.05-2.15(2H，m)，3.05-3.15(2H，m)，3.15-3.25(2H，m)，4.19(2H，q，J＝7.0)，4.40(2H，s)，4.45(2H，d，J＝6.0)，4.78(1H，m)，6.38(1H，dt，J＝16.0，6.0)，6.66(1H，d，J＝16.0)，7.04(1H，d，J＝9.0)，7.31(1H，d，J＝9.0)，7.38(1H，dd，J＝9.0，3.0)，7.56(1H，d，J＝3.0)，7.62(1H，dd，J＝9.0，2.0)，7.94(1H，d，J＝2.0)。
(b) N-(4-(1-acetimidoyl piperidin-4-yl oxygen)-3-chloro-phenyl-)-N-(3-(5-amidino groups-2-hydroxy phenyl)-2-(E)-propenyl) sulphonamide ethyl acetate dihydrochloride
N-(3-(5-amidino groups-2-hydroxy phenyl)-2-(E)-propenyl)-N-(3-chloro-4-(piperidin-4-yl oxygen) phenyl) sulphonamide ethyl acetate (0.05g) is dissolved in the ethanol (10ml), at ice-cooled lower adding iminoester hydrochloride (0.04g) and triethylamine (0.08ml), at room temperature stir after 5 hours and placed 13 hours.With the reaction mixture concentrating under reduced pressure, residue preparative HPLC (YMC-Pack ODS YMC, elutriant: 20% acetonitrile solution) refining, the gained amorphous solid is dissolved in the ethanol (10ml), add 4M hydrogenchloride ethyl acetate solution (0.05ml), then under reduced pressure be concentrated into dried.Obtain colourless amorphous solid title compound 0.04g (yield 59%).
1H?NMR(500MHz，DMSO-d 6)δppm：1.23(3H，t，J＝7.0)，1.70-1.85(2H，m)，2.00-2.15(2H，m)，2.30(3H，s)，3.50-3.80(4H，m)，4.19(2H，q，J＝7.0)，4.41(2H，s)，4.45(2H，d，J＝6.0)，4.84(1H，m)，6.39(1H，dt，J＝16.0，6.0)，6.65(1H，d，J＝16.0)，7.08(1H，d，J＝9.0)，7.33(1H，d，J＝9.0)，7.38(1H，dd，J＝9.0，2.0)，7.56(1H，d，J＝2.0)，7.63(1H，dd，J＝9.0，2.0)，7.95(1H，d，J＝2.0)；
IR(KBr，cm -1)：1738，1671。
Embodiment 42
N-(4-(1-acetimidoyl piperidin-4-yl oxygen)-5-formamyl-3-chloro-phenyl-)-N-(3-(3-carbamimido-phenyl)-2-(E)-propenyl) sulphonamide ethyl acetate dihydrochloride (exemplary compounds number: 1484)
(a) N-(3-(3-carbamimido-phenyl)-2-(E)-propenyl)-N-(5-formamyl-3-chloro-4-(piperidin-4-yl oxygen) phenyl) sulphonamide ethyl acetate dihydrochloride
N-(4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-5-formamyl-3-chloro-phenyl-)-N-(3-(3-cyano-phenyl)-2-(E)-propenyl) sulphonamide ethyl acetate (1.50g) is dissolved in the mixed solvent of methylene dichloride (20ml) and ethanol (20ml); passed into hydrogenchloride 1.5 hours under ice-cooled, the gained mixture at room temperature stirred in the reactor of jam-pack 4 hours.With the reaction mixture concentrating under reduced pressure, the gained residue is dissolved in the ethanol (20ml), adds aqueous ammonium chloride solution (0.26g is dissolved in the 5ml water) and 28% ammoniacal liquor (0.60ml), at room temperature stirs 4 hours, then places 12 hours.With the reaction mixture concentrating under reduced pressure, (YMC-Pack ODS YMC, elutriant: 20% acetonitrile solution) refining, the gained amorphous solid is dissolved in the 1 M hydrochloric acid residue, then under reduced pressure is concentrated into dried with HPLC.Obtain colourless amorphous solid title compound 0.55g (yield 37%).
1H?NMR(500MHz，DMSO-d 6)δppm：1.23(3H，t，J＝7.0)，1.90-2.00(2H，m)，2.00-2.10(2H，m)，2.95-3.05(2H，m)，3.20-3.30(2H，m)，4.19(2H，q，J＝7.0)，4.35(1H，m)，4.48(2H，s)，4.51(2H，d，J＝6.0)，6.44(1H，dt，J＝16.0，6.0)，6.62(1H，d，J＝16.0)，7.50-7.60(2H，m)，7.65-7.80(3H，m)，7.88(1H，m)；
IR(KBr，cm -1)：1737，1672。
(b) N-(4-(1-acetimidoyl piperidin-4-yl oxygen)-5-formamyl-3-chloro-phenyl-)-N-(3-(3-carbamimido-phenyl)-2-(E)-propenyl) sulphonamide ethyl acetate dihydrochloride
N-(3-(3-carbamimido-phenyl)-2-(E)-propenyl)-N-(5-formamyl-3-chloro-4-(piperidin-4-yl oxygen) phenyl) sulphonamide ethyl acetate dihydrochloride (0.51g) is dissolved in the ethanol (25ml); at ice-cooled lower adding iminoester hydrochloride (0.30g) and triethylamine (0.70ml), at room temperature stir after 1 hour and placed 12 hours.With the reaction mixture concentrating under reduced pressure, residue preparative HPLC (YMC-Pack ODSYMC, elutriant: 20% acetonitrile solution) refining, the gained amorphous solid is dissolved in the ethanol (10ml), add 4M hydrogenchloride ethyl acetate solution (0.50ml), then under reduced pressure be concentrated into dried.Obtain colourless amorphous solid title compound 0.36g (yield 66%).
1H?NMR(500MHz，DMSO-d 6)δppm：1.23(3H，t，J＝7.0)，1.75-1.90(2H，m)，1.90-2.05(2H，m)，2.29(3H，s)，3.40-3.55(2H，m)，3.75-3.90(2H，m)，4.20(2H，q，J＝7.0)，4.42(1H，m)，4.48(2H，s)，4.52(2H，d，J＝6.0)，6.44(1H，dt，J＝16.0，6.0)，6.62(1H，d，J＝16.0)，7.50-7.60(2H，m)，7.65-7.80(3H，m)，7.89(1H，m)；
IR(KBr，cm -1)：1738，1671，1622。
Embodiment 43
N-(4-(1-acetimidoyl piperidin-4-yl oxygen)-5-formamyl-3-chloro-phenyl-)-N-(3-(3-carbamimido-phenyl)-2-(E)-propenyl) sulphonamide acetic acid dihydrochloride (exemplary compounds number: 2013)
N-(4-(1-acetimidoyl piperidin-4-yl oxygen)-5-formamyl-3-chloro-phenyl-)-N-(3-(3-carbamimido-phenyl)-2-(E)-propenyl) sulphonamide ethyl acetate dihydrochloride (0.20g) is dissolved in the 3M hydrochloric acid (20ml), stirs 1.5 hours at 70 ℃.Reaction mixture carries out concentrating under reduced pressure after being cooled to room temperature, residue preparative HPLC (YMC-Pack ODS YMC, elutriant: 15% acetonitrile solution) refining, the gained amorphous solid is dissolved in the 1M hydrochloric acid (0.80ml), then under reduced pressure be concentrated into driedly, obtain colourless amorphous solid title compound 0.16g (yield 83%).
1H?NMR(500MHz，DMSO-d 6)δppm：1.75-1.90(2H，m)，1.90-2.05(2H，m)，2.28(3H，s)，3.40-3.55(2H，m)，3.75-3.90(2H，m)，4.35(2H，s)，4.42(1H，m)，4.51(2H，d，J＝6.0)，6.44(1H，dt，J＝16.0，6.0)，6.61(1H，d，J＝16.0)，7.50-7.60(2H，m)，7.65-7.80(3H，m)，7.87(1H，m)；
IR(KBr，cm -1)：1730，1671，1628。
Embodiment 44
N-(4-(1-acetimidoyl piperidin-4-yl oxygen)-3-formamyl-5-aminomethyl phenyl)-N-(3-(3-carbamimido-phenyl)-2-(E)-propenyl) sulphonamide ethyl acetate dihydrochloride (exemplary compounds number: 1498)
(a) N-(3-(3-carbamimido-phenyl)-2-(E)-propenyl)-N-(3-formamyl-5-methyl-4-(piperidin-4-yl oxygen) phenyl) sulphonamide ethyl acetate dihydrochloride
N-(4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-3-formamyl-5-aminomethyl phenyl)-N-(3-(3-cyano-phenyl)-2-(E)-propenyl) sulphonamide ethyl acetate (3.20g) is dissolved in the mixed solvent of methylene dichloride (30ml) and ethanol (30ml); passed into hydrogenchloride 1.5 hours under ice-cooled, the gained mixture at room temperature stirred in the reactor of jam-pack 2.5 hours.With the reaction mixture concentrating under reduced pressure, the gained residue is dissolved in the ethanol (30ml), adds aqueous ammonium chloride solution (0.59g is dissolved in the 8ml water) and 28% ammoniacal liquor (1.34ml), at room temperature stirs 0.5 hour, then places 15 hours.With the reaction mixture concentrating under reduced pressure, residue HPLC (YMC-Pack ODS YMC, elutriant: 20% acetonitrile solution) refining, the gained amorphous solid is dissolved in the ethanol (10ml), add 4M hydrogenchloride dioxane solution (3.00ml), then under reduced pressure be concentrated into dried.Obtain colourless amorphous solid title compound 2.85g (yield 90%).
1H?NMR(500MHz，DMSO-d 6)δppm：1.23(3H，t，J＝7.0)，1.85-1.95(2H，m)，1.95-2.05(2H，m)，2.26(3H，s)，2.90-3.00(2H，m)，3.20-3.30(2H，m)，4.15-4.20(1H，m)，4.20(2H，q，J＝7.0)，4.39(2H，s)，4.47(2H，d，J＝6.0)，6.43(1H，dt，J＝16.0，6.0)，6.60(1H，d，J＝16.0)，7.54(2H，m)，7.57(1H，m)，7.68(1H，m)，7.73(1H，m)，7.87(1H，m)；
IR(KBr，cm -1)：1737，1672。
(b) N-(4-(1-acetimidoyl piperidin-4-yl oxygen)-3-formamyl-5-aminomethyl phenyl)-N-(3-(3-carbamimido-phenyl)-2-(E)-propenyl) sulphonamide ethyl acetate dihydrochloride
N-(3-(3-carbamimido-phenyl)-2-(E)-propenyl)-N-(3-formamyl-5-methyl-4-(piperidin-4-yl oxygen) phenyl) sulphonamide ethyl acetate dihydrochloride (2.68g) is dissolved in the ethanol (40ml); at ice-cooled lower adding iminoester hydrochloride (1.58g) and triethylamine (3.5ml), at room temperature stir after 1 hour and placed 13 hours.With the reaction mixture concentrating under reduced pressure, residue preparative HPLC (YMC-Pack ODSYMC, elutriant: 20% acetonitrile solution) refining, the gained amorphous solid is dissolved in the ethanol (10ml), add 4M hydrogenchloride dioxane solution (0.44ml), then under reduced pressure be concentrated into dried.Obtain colourless amorphous solid title compound 0.3 8g (yield 13%).
1H?NMR(500MHz，DMSO-d 6)δ?ppm：1.23(3H，t，J＝7.0)，1.70-1.90(2H，m)，1.90-2.00(2H，m)，2.27(3H，s)，2.29(3H，s)，3.3?5-3.45(2H，m)，3.75-3.95(2H，m)，4.20(2H，q，J＝7.0)，4.25(1?H，m)，4.40(2H，s)，4.48(2H，d，J＝6.0)，6.43(1H，dt，J＝16.0，6.0)，6.60(1H，d，J＝16.0)，7.43(2H，m)，7.55(1H，m)，7.69(1H，m)，7.73(1H，m)，7.88(1H，m)；
IR(KBr，cm -1)：1738，1672，1625。
Embodiment 45
N-(4-(1-acetimidoyl piperidin-4-yl oxygen)-3-formamyl-5-aminomethyl phenyl)-N-(3-(3-carbamimido-phenyl)-2-(E)-propenyl) sulphonamide acetic acid dihydrochloride (exemplary compounds number: 2027)
N-(4-(1-acetimidoyl piperidin-4-yl oxygen)-3-formamyl-5-aminomethyl phenyl)-N-(3-(3-carbamimido-phenyl)-2-(E)-propenyl) sulphonamide ethyl acetate dihydrochloride (0.24g) is dissolved in the 3M hydrochloric acid (20ml), stirs 2.5 hours at 70 ℃.Reaction mixture carries out concentrating under reduced pressure after being cooled to room temperature, residue preparative HPLC (YMC-Pack ODS YMC, elutriant: 15% acetonitrile solution) refining, the gained amorphous solid is dissolved in the 1 M hydrochloric acid (1.00ml), then under reduced pressure be concentrated into driedly, obtain colourless amorphous solid title compound 0.18g (yield 78%).
1H?NMR(500MHz，DMSO-d 6)δppm：1.70-1.85(2H，m)，1.90-2.00(2H，m)，2.27(3H，s)，2.29(3H，s)，3.30-3.45(2H，m)，3.75-3.90(2H，m)，4.25(1H，m)，4.27(2H，s)，4.48(2H，d，J＝6.0)，6.43(1H，dt，J＝16.0，6.0)，6.60(1H，d，J＝16.0)，7.43(2H，m)，7.55(1H，m)，7.67(1H，m)，7.72(1H，m)，7.86(1H，m)；
IR(KBr，cm -1)：1731，1672。
Embodiment 46
N-(4-(1-acetimidoyl piperidin-4-yl oxygen)-3,5-difluorophenyl)-N-(3-(3-carbamimido-phenyl)-2-(E)-propenyl) sulphonamide ethyl acetate dihydrochloride (exemplary compounds number: 1474)
(a) N-(3-(3-carbamimido-phenyl)-2-(E)-propenyl)-N-(3,5-, two fluoro-4-(piperidin-4-yl oxygen) phenyl) sulphonamide ethyl acetate dihydrochloride
N-(4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-3, the 5-difluorophenyl)-N-(3-(3-cyano-phenyl)-2-(E)-propenyl) sulphonamide ethyl acetate (1823mg) is dissolved in the mixed solvent of methylene dichloride (30ml) and ethanol (15ml), passed into hydrogenchloride 1 hour under ice-cooled, the gained mixture at room temperature stirred in the reactor of jam-pack 5.5 hours.With the reaction mixture concentrating under reduced pressure, the gained residue is dissolved in the ethanol (20ml); Add aqueous ammonium chloride solution (315mg is dissolved in the 10ml water) and 28% ammoniacal liquor (0.59ml), at room temperature placed 15 hours.In reaction mixture, add 4M hydrogenchloride dioxane solution (1ml), then concentrating under reduced pressure, residue HPLC (YMC-Pack ODS YMC, elutriant: 20% acetonitrile solution) refining, the gained amorphous solid is dissolved in the ethanol (20ml), add 1M hydrochloric acid (2ml), then under reduced pressure be concentrated into dried.Obtain colourless amorphous solid title compound 1214mg (yield 68%).
1H?NMR(400MHz，DMSO-d 6)δppm：1.21(3H，t，J＝7.0)，1.85-1.91(2H，m)，2.04-2.10(2H，m)，2.99-3.05(2H，m)，3.18-3.24(2H，m)，4.18(2H，q，J＝7.0)，4.37(1H，m)，4.50(2H，s)，4.51(2H，d，J＝6.0)，6.42(1H，dt，J＝16.0，6.0)，6.62(1H，d，J＝16.0)，7.39(2H，m)，7.55(1H，t，J＝8.0)，7.68(1H，d，J＝8.0)，7.74(1H，d，J＝8.0)，7.88(1H，s)；
IR(KBr，cm -1)：1738，1676。
(b) N-(4-(1-acetimidoyl piperidin-4-yl oxygen)-3,5-difluorophenyl)-N-(3-(3-carbamimido-phenyl)-2-(E)-propenyl) sulphonamide ethyl acetate dihydrochloride
N-(3-(3-carbamimido-phenyl)-2-(E)-propenyl)-N-(3,5-two fluoro-4-(piperidin-4-yl oxygen) phenyl) sulphonamide ethyl acetate dihydrochloride (1020mg) is dissolved in the ethanol (30ml), at ice-cooled lower adding iminoester hydrochloride (620mg) and triethylamine (1.17ml), at room temperature stirred 15 hours.In reaction mixture, add 4M hydrogenchloride dioxane solution (1.0ml), then concentrating under reduced pressure, residue preparative HPLC (YMC-Pack ODS YMC, elutriant: 22% acetonitrile solution) refining, the gained amorphous solid is dissolved in the ethanol (15ml), adds 1M hydrochloric acid (1.0ml), then under reduced pressure is concentrated into dried, in its water-soluble (approximately 20ml), after lyophilize, obtain colourless amorphous solid title compound 851mg (yield 78%).
1H?NMR(400MHz，DMSO-d 6)δppm：1.22(3H，t，J＝7.0)，1.76-1.83(2H，m)，1.98-2.03(2H，m)，2.30(3H，s)，3.52(2H，m)，3.78(2H，m)，4.18(2H，q，J＝7.0)，4.46(1H，m)，4.51(2H，s)，4.52(2H，d，J＝6.0)，6.43(1H，dt，J＝16.0，6.0)，6.62(1H，d，J＝16.0)，7.39(2H，m)，7.55(1H，t，J＝8.0)，7.70(1H，d，J＝8.0)，7.73(1H，d，J＝8.0)，7.91(1H，s)；
IR(KBr，cm -1)：1739，1673，1624。
Embodiment 47
N-(4-(1-acetimidoyl piperidin-4-yl oxygen)-3,5-difluorophenyl)-N-(3-(3-carbamimido-phenyl)-2-(E)-propenyl) sulphonamide acetic acid dihydrochloride (exemplary compounds number: 2003)
N-(4-(1-acetimidoyl piperidin-4-yl oxygen)-3; the 5-difluorophenyl)-and N-(3-(3-carbamimido-phenyl)-2-(E)-propenyl) sulphonamide ethyl acetate dihydrochloride (415mg) is dissolved in the 2M hydrochloric acid (20ml), stirred 5 hours at 60 ℃.Reaction mixture carries out concentrating under reduced pressure after being cooled to room temperature, residue preparative HPLC (YMC-Pack ODS YMC, elutriant: 15% acetonitrile solution) refining, the gained amorphous solid is dissolved in 15% acetonitrile solution (20ml), add 1M hydrochloric acid (1.0ml), then under reduced pressure be concentrated into dried.The gained amorphous solid is dissolved in the water (approximately 20ml), obtains colourless amorphous solid title compound 319mg (yield 80%) after lyophilize.
1H?NMR(400MHz，DMSO-d 6)δppm：1.70-1.90(2H，m)，1.95-2.10(2H，m)，2.29(3H，s)，3.40-3.60(2H，m)，3.78(2H，m)，4.37(2H，s)，4.46(1H，m)，4.52(2H，d，J＝6.0)，6.43(1H，dt，J＝16.0，6.0)，6.62(1H，d，J＝16.0)，7.38(2H，m)，7.55(1H，t，J＝8.0)，7.69(1H，d，J＝8.0)，7.74(1H，d，J＝8.0)，7.89(1H，s)；
IR(KBr，cm -1)：3123，1733，1674，1626。
Embodiment 48
N-(4-(1-acetimidoyl piperidin-4-yl oxygen)-3,5-dichlorophenyl)-N-(3-(3-carbamimido-phenyl)-2-(E)-propenyl) sulphonamide ethyl acetate dihydrochloride (exemplary compounds number: 1478)
(a) N-(3-(3-carbamimido-phenyl)-2-(E)-propenyl)-N-(3,5-, two chloro-4-(piperidin-4-yl oxygen) phenyl) sulphonamide ethyl acetate dihydrochloride
N-(4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-3, the 5-dichlorophenyl)-N-(3-(3-cyano-phenyl)-2-(E)-propenyl) sulphonamide ethyl acetate (2057mg) is dissolved in the mixed solvent of methylene dichloride (30ml) and ethanol (15ml), passed into hydrogenchloride 1 hour under ice-cooled, the gained mixture at room temperature stirred in the reactor of jam-pack 6 hours.With the reaction mixture concentrating under reduced pressure, the gained residue is dissolved in the ethanol (40ml), adds aqueous ammonium chloride solution (337mg is dissolved in the 20ml water) and 28% ammoniacal liquor (0.63ml), then at room temperature places 15 hours.In reaction mixture, add 4M hydrogenchloride dioxane solution (2ml), then concentrating under reduced pressure.(YMC-Pack ODSYMC, elutriant: 23% acetonitrile solution) refining, the amorphous solid that obtains is dissolved in the ethanol (20ml) residue, adds 1M hydrochloric acid (1ml), then under reduced pressure is concentrated into dried with preparative HPLC.Obtain colourless amorphous solid title compound 1002mg (yield 49%).
1H?NMR(400MHz，DMSO-d 6)δppm：1.21(3H，t，J＝7.0)，1.95-2.15(4H，m)，2.95-3.10(2H，m)，3.20-3.35(2H，m)，4.18(2H，q，J＝7.0)，4.46(1H，m)，4.53(4H，m)，6.43(1H，dt，J＝16.0，6.0)，6.62(1H，d，J＝16.0)，7.55(1H，t，J＝7.5)，7.67(2H，s)，7.68(1H，d，J＝7.5)，7.74(1H，d，J＝7.5)，7.88(1H，s)；
IR(KBr，cm -1)：1738，1676。
(b) N-(4-(1-acetimidoyl piperidin-4-yl oxygen)-3,5-dichlorophenyl)-N-(3-(3-carbamimido-phenyl)-2-(E)-propenyl) sulphonamide ethyl acetate dihydrochloride
N-(3-(3-carbamimido-phenyl)-2-(E)-propenyl)-N-(3,5-two chloro-4-(piperidin-4-yl oxygen) phenyl) sulphonamide ethyl acetate dihydrochloride (800mg) is dissolved in the ethanol (30ml), add iminoester hydrochloride (462mg) and triethylamine (0.87ml), then at room temperature stirred 15 hours.In reaction mixture, add 4M hydrogenchloride dioxane solution (1ml), then concentrating under reduced pressure.(YMC-Pack ODS YMC, elutriant: 25% acetonitrile solution) refining, the gained amorphous solid is dissolved in the ethanol (20ml) residue, adds 1M hydrochloric acid (1.0ml), then is evaporated to dried with preparative HPLC.In the gained amorphous solid water-soluble (approximately 20ml), after lyophilize, obtain colourless amorphous solid title compound 722mg (yield 85%).
1H?NMR(500MHz，DMSO-d 6)δppm：1.22(3H，t，J＝7.0)，1.80-2.00(2H，m)，2.00-2.10(2H，m)，2.29(3H，s)，3.40-3.55(2H，m)，3.80-4.00(2H，m)，4.18(2H，q，J＝7.0)，4.53(5H，m)，6.43(1H，dt，J＝16.0，6.0)，6.63(1H，d，J＝16.0)，7.56(1H，t，J＝8.0)，7.67(2H，s)，7.68(1H，d，J＝8.0)，7.74(1H，d，J＝8.0)，7.88(1H，s)；
IR(KBr，cm -1)：1739，1674，1624。
Embodiment 49
N-(4-(1-acetimidoyl piperidin-4-yl oxygen)-3,5-dichlorophenyl)-N-(3-(3-carbamimido-phenyl)-2-(E)-propenyl) sulphonamide acetic acid dihydrochloride (exemplary compounds number: 2007)
N-(4-(1-acetimidoyl piperidin-4-yl oxygen)-3; the 5-dichlorophenyl)-and N-(3-(3-carbamimido-phenyl)-2-(E)-propenyl) sulphonamide ethyl acetate dihydrochloride (300mg) is dissolved in the 2M hydrochloric acid (20ml), stirred 6 hours at 60 ℃.Reaction mixture carries out concentrating under reduced pressure after being cooled to room temperature, residue preparative HPLC (YMC-Pack ODS YMC, elutriant: 18% acetonitrile solution) refining, the gained amorphous solid is dissolved in 18% acetonitrile solution (20ml), add 1M hydrochloric acid (1ml), then under reduced pressure be concentrated into dried.Residue is dissolved in the water (approximately 20ml), obtains colourless amorphous solid title compound 233mg (yield 81%) after lyophilize.
1H?NMR(500MHz，DMSO-d 6)δppm：1.80-2.00(2H，m)，2.00-2.10(2H，m)，2.30(3H，s)，3.40-3.55(2H，m)，3.80-4.00(2H，m)，4.39(2H，s)，4.53(2H，d，J＝6.0)，4.53(1H，m)，6.44(1H，dt，J＝16.0，6.0)，6.62(1H，d，J＝16.0)，7.56(1H，t，J＝8.0)，7.67(2H，s)，7.70(1H，d，J＝8.0)，7.74(1H，d，J＝8.0)，7.90(1H，s)；
IR(KBr，cm -1)：3127，1733，1673，1625。
Embodiment 50
N-(4-(1-acetimidoyl piperidin-4-yl oxygen)-3,5-3,5-dimethylphenyl)-N-(3-(3-carbamimido-phenyl)-2-(E)-propenyl) sulphonamide methyl acetate dihydrochloride (exemplary compounds number: 2429)
(a) N-(3-(3-carbamimido-phenyl)-2-(E)-propenyl)-N-(3,5-dimethyl-4-(piperidin-4-yl oxygen) phenyl) sulphonamide ethyl acetate dihydrochloride
N-(4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-3, the 5-3,5-dimethylphenyl)-N-(3-(3-cyano-phenyl)-2-(E)-propenyl) sulphonamide ethyl acetate (1.75g) is dissolved in the mixed solvent of methylene dichloride (30ml) and ethanol (15ml), passed into hydrogenchloride 1 hour under ice-cooled, the gained mixture at room temperature stirred in the reactor of jam-pack 6 hours.With the reaction mixture concentrating under reduced pressure, the gained residue is dissolved in the ethanol (30ml), adds aqueous ammonium chloride solution (0.31g is dissolved in the 15ml water) and 28% ammoniacal liquor (0.57ml), at room temperature places 14 hours.In reaction mixture, add 4M hydrogenchloride dioxane solution (1ml), then concentrating under reduced pressure, residue HPLC (YMC-Pack ODS YMC, elutriant: 20% acetonitrile solution) refining, the gained amorphous solid is dissolved in the ethanol (20ml), add 1 M hydrochloric acid (1ml), then under reduced pressure be concentrated into dried.Obtain colourless amorphous solid title compound 1.21g (yield 70%).
1H?NMR(400MHz，DMSO-d 6)δppm：1.23(3H，t，J＝7.0)，1.80-1.95(2H，m)，2.00-2.10(2H，m)，2.22(6H，s)，2.94(2H，m)，3.26(2H，m)，4.12(1H，m)，4.19(2H，q，J＝7.0)，4.35(2H，s)，4.44(2H，d，J＝6.0)，6.43(1H，dt，J＝16.0，6.0)，6.59(1H，d，J＝16.0)，7.17(2H，s)，7.55(1H，t，J＝8.0)，7.68(1H，d，J＝8.0)，7.73(1H，d，J＝8.0)，7.88(1H，s)；
IR(KBr，cm -1)：1738，1676。
(b) N-(4-(1-acetimidoyl piperidin-4-yl oxygen)-3,5-3,5-dimethylphenyl)-N-(3-(3-carbamimido-phenyl)-2-(E)-propenyl) sulphonamide methyl acetate dihydrochloride
N-(3-(3-carbamimido-phenyl)-2-(E)-propenyl)-N-(3,5-dimethyl-4-(piperidin-4-yl oxygen) phenyl) sulphonamide ethyl acetate dihydrochloride (1.00g) is dissolved in the ethanol (30ml), at ice-cooled lower adding iminoester hydrochloride (0.62g) and triethylamine (1.16ml), at room temperature stirred 14 hours.In reaction mixture, add 4M hydrogenchloride dioxane solution (2ml), then concentrating under reduced pressure, residue preparative HPLC (YMC-Pack ODS YMC, elutriant: 20% acetonitrile solution) refining, the gained amorphous solid is dissolved in the methyl alcohol (20ml), add 1M hydrochloric acid (1.0ml), then under reduced pressure be concentrated into dried.In the gained residue water-soluble (approximately 20ml), after lyophilize, obtain colourless amorphous solid title compound 0.81g (yield 78%).
1H?NMR(400MHz，DMSO-d 6)δ?ppm：1.75(2H，m)，1.98(2H，m)，2.23(6H，s)，2.29(3H，s)，3.25-3.35(2H，m)，3.73(3H，s)，3.85(1H，m)，4.02(1H，m)，4.18(1H，m)，4.38(2H，s)，4.44(2H，d，J＝6.0)，6.42(1H，dt，J＝16.0，6.0)，6.59(1H，d，J＝16.0)，7.1?6(2H，s)，7.55(1H，t，J＝8.0)，7.68(1H，d，J＝8.0)，7.73(1H，d，J＝8.0)，7.88(1H，s)；
IR(KBr，cm -1)：1743，1673，1626。
Embodiment 51
N-(4-(1-acetimidoyl piperidin-4-yl oxygen)-3,5-3,5-dimethylphenyl)-N-(3-(3-carbamimido-phenyl)-2-(E)-propenyl) sulphonamide acetic acid dihydrochloride (exemplary compounds number: 2011)
N-(4-(1-acetimidoyl piperidin-4-yl oxygen)-3; the 5-3,5-dimethylphenyl)-and N-(3-(3-carbamimido-phenyl)-2-(E)-propenyl) sulphonamide methyl acetate dihydrochloride (620mg) is dissolved in the 2M hydrochloric acid (20ml), stirred 5 hours at 60 ℃.Reaction mixture carries out concentrating under reduced pressure after being cooled to room temperature, residue preparative HPLC (YMC-Pack ODS YMC, elutriant: 18% acetonitrile solution) refining, the gained amorphous solid is dissolved in 18% acetonitrile solution (20ml), add 1 M hydrochloric acid (1.0ml), then under reduced pressure be concentrated into dried.Residue is dissolved in the water (approximately 20ml), obtains colourless amorphous solid title compound 220mg (yield 57%) after lyophilize.
1H?NMR(500MHz，DMSO-d 6)δppm：1.75(2H，m)，1.98(2H，m)，2.23(6H，s)，2.29(3H，s)，3.25-3.40(2H，m)，3.85(1H，m)，4.02(1H，m)，4.17(1H，m)，4.22(2H，s)，4.44(2H，d，J＝6.0)，6.43(1H，dt，J＝16.0，6.0)，6.58(1H，d，J＝16.0)，7.17(2H，s)，7.55(1H，t，J＝8.0)，7.69(1H，d，J＝8.0)，7.72(1H，d，J＝8.0)，7.88(1H，s)；
IR(KBr，cm -1)：3131，1733，1673，1626。
Embodiment 52
4-(N-(4-(1-acetimidoyl piperidin-4-yl oxygen) phenyl)-N-(3-(3-carbamimido-phenyl)-2-(E)-propenyl) amino) ethyl butyrate tri hydrochloride (exemplary compounds number: 849)
(a) 4-(N-(3-(3-carbamimido-phenyl)-2-(E)-propenyl)-N-(4-(piperidin-4-yl oxygen) phenyl) amino) ethyl butyrate tri hydrochloride
4-(N-(4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen) phenyl)-N-(3-(3-cyano-phenyl)-2-(E)-propenyl) amino) ethyl butyrate (2.19g) is dissolved in the mixed solvent of methylene dichloride (30ml) and ethanol (15ml), passed into hydrogenchloride 1 hour under ice-cooled, the gained mixture at room temperature stirred in the reactor of jam-pack 5 hours.With the reaction mixture concentrating under reduced pressure, the gained residue is dissolved in the ethanol (20ml), adds aqueous ammonium chloride solution (0.48g is dissolved in the 10ml water) and 28% ammoniacal liquor (1.04ml), at room temperature places 14 hours.In reaction mixture, add 4M hydrogenchloride dioxane solution (1ml), then concentrating under reduced pressure, residue HPLC (YMC-Pack ODS YMC, elutriant: 25% acetonitrile solution) refining, the gained amorphous solid is dissolved in the ethanol (20ml), add 1M hydrochloric acid (1.0ml), then under reduced pressure be concentrated into dried.In the gained residue water-soluble (approximately 10ml), after lyophilize, obtain faint yellow amorphous solid title compound 1.52g (yield 66%).
1H?NMR(400MHz，DMSO-d 6)δppm：1.19(3H，t，J＝7.0)，1.70-1.95(4H，m)，2.00-2.15(2H，m)，2.39(2H，m)，3.00-3.15(2H，m)，3.15-3.30(2H，m)，3.30-3.40(2H，m)，4.07(2H，q，J＝7.0)，4.00-4.20(2H，m)，4.43(1H，m)，6.52(1H，dt，J＝16.0，5.5)，6.55-7.00(5H，m)，7.59(1H，t，J＝8.0)，7.65-7.80(2H，m)，7.88(1H，s)；
IR(KBr，cm -1)：1728，1674。
(b) 4-(N-(4-(1-acetimidoyl piperidin-4-yl oxygen) phenyl)-N-(3-(3-carbamimido-phenyl)-2-(E)-propenyl) amino) ethyl butyrate tri hydrochloride
4-(N-(3-(3-carbamimido-phenyl)-2-(E)-propenyl)-N-(4-(piperidin-4-yl oxygen) phenyl) amino) ethyl butyrate tri hydrochloride (1378mg) is dissolved in the ethanol (20ml), add iminoester hydrochloride (890mg) and triethylamine (2.01ml), at room temperature stirred 4 hours.In reaction mixture, add 4M hydrogenchloride dioxane solution (1ml), then concentrating under reduced pressure, residue preparative HPLC (YMC-PackODS YMC, elutriant: 25% acetonitrile solution) refining, the gained amorphous solid is dissolved in the ethanol (20ml), add 1M hydrochloric acid (1.0ml), then under reduced pressure be concentrated into dried.In the gained residue water-soluble (approximately 20ml), after lyophilize, obtain faint yellow amorphous solid title compound 1072mg (yield 73%).
1H?NMR(400MHz，DMSO-d 6)δppm：1.16(3H，t，J＝7.0)，1.60-1.90(4H，m)，1.90-2.10(2H，m)，2.29(3H，s)，2.30-2.40(2H，m)，3.20-3.40(2H，m)，3.45-3.60(2H，m)，3.70-3.85(2H，m)，4.04(2H，q，J＝7.0)，4.00-4.10(2H，m)，4.40-4.55(1H，m)，6.49(1H，dt，J＝16.0，6.0)，6.55-6.95(5H，m)，7.57(1H，t，J＝7.5)，7.65-7.75(2H，m)，7.85(IH，s)；
IR(KBr，cm -1)：1727，1673，1624。
Embodiment 53
4-(N-(4-(1-acetimidoyl piperidin-4-yl oxygen) phenyl)-N-(3-(3-carbamimido-phenyl)-2-(E)-propenyl) amino) butyric acid tri hydrochloride (exemplary compounds number: 663)
4-(N-(4-(1-acetimidoyl piperidin-4-yl oxygen) phenyl)-N-(3-(3-carbamimido-phenyl)-2-(E)-propenyl) amino) ethyl butyrate tri hydrochloride (572mg) is dissolved in the 2M hydrochloric acid (20ml); at room temperature stirred 2 hours, and then stirred 2 hours at 50 ℃.Reaction mixture carries out concentrating under reduced pressure after being cooled to room temperature, residue preparative HPLC (YMC-Pack ODS YMC, elutriant: 18% acetonitrile solution) refining, the gained amorphous solid is dissolved in the mixture of 18% acetonitrile solution (20ml) and 1M hydrochloric acid (1.0ml), then under reduced pressure is concentrated into dried.Residue is dissolved in the water (approximately 20ml), obtains light brown amorphous solid title compound 333mg (yield 61%) after lyophilize.
1H?NMR(400MHz，DMSO-d 6)δppm：1.40-1.95(4H，m)，1.95-2.10(2H，m)，2.30(3H，s)，2.25-2.35(2H，m)，3.45-4.40(8H，m)，4.65-4.80(1H，m)，6.50(1H，dt，J＝15.5，6.5)，6.55-7.30(5H，m)，7.58(1H，t，J＝7.5)，7.65-7.75(2H，m)，7.85(1H，s)；
IR(KBr，cm -1)：3119，1726，1673，1625。
Embodiment 54
N-(4-(1-acetimidoyl piperidin-4-yl oxygen)-3-trifluoromethyl)-N-(3-(3-carbamimido-phenyl)-2-(E)-propenyl) sulphonamide acetic acid dihydrochloride (exemplary compounds number: 1969)
N-(4-(1-acetimidoyl piperidin-4-yl oxygen)-3-trifluoromethyl)-N-(3-(3-carbamimido-phenyl)-2-(E)-propenyl) sulphonamide ethyl acetate dihydrochloride (321mg) is dissolved in the 3M hydrochloric acid (15ml), stirs 3 hours at 80 ℃.Reaction mixture carries out concentrating under reduced pressure after being cooled to room temperature, residue preparative HPLC (YMC-Pack ODS YMC, elutriant: 20% acetonitrile solution) refining, the gained amorphous solid is dissolved in the methyl alcohol (10ml), add 4M hydrogenchloride dioxane solution (0.5ml), then under reduced pressure be concentrated into dried.Residue is dissolved in the water (approximately 15ml), obtains colourless amorphous solid title compound 231mg (yield 75%) after lyophilize.
1H?NMR(500MHz，DMSO-d 6)δppm：1.79(2H，m)，2.05(2H，m)，2.31(3H，s)，3.40-3.75(4H，m)，4.32(2H，s)，4.50(2H，d，J＝6.5)，4.96(1H，m)，6.47(1H，dt，J＝17.0，6.5)；6.57(1H，d，J＝17.0)，7.43(1H，d，J＝10.0)，7.54(1H，d，J＝7.5)，7.71(4H，m)，7.92(1H，s)；
IR(KBr，cm -1)：3102，1734，1675，1617。
Embodiment 55
N-(4-(1-acetimidoyl piperidin-4-yl oxygen)-3-aminomethyl phenyl)-N-(3-(3-carbamimido-phenyl)-2-(E)-propenyl) sulphonamide acetic acid dihydrochloride (exemplary compounds number: 1949)
N-(4-(1-acetimidoyl piperidin-4-yl oxygen)-3-aminomethyl phenyl)-N-(3-(3-carbamimido-phenyl)-2-(E)-propenyl) sulphonamide ethyl acetate dihydrochloride (480mg) is dissolved in the 3M hydrochloric acid (15ml), stirs 3 hours at 80 ℃.Reaction mixture carries out concentrating under reduced pressure after being cooled to room temperature, residue preparative HPLC (YMC-Pack ODS YMC, elutriant: 20% acetonitrile solution) refining, the gained amorphous solid is dissolved in the methyl alcohol (15ml), add 4M hydrogenchloride dioxane solution (0.5ml), then under reduced pressure be concentrated into dried.Obtain colourless amorphous solid title compound 315mg (yield 69%).
1H?NMR(500MHz，DMSO-d 6)δppm：1.78(2H，m)，2.02(2H，m)，2.14(3H，s)，2.29(3H，s)，3.62(4H，m)，3.71(2H，s)，4.12(1H，m)，4.46(2H，d，J＝6.0)，4.70(1H，m)，6.45(1H，dt，J＝16.0，6.0)，6.50(1H，d，J＝16.0)，7.02(1H，d，J＝8.5)，7.36(1H，s)，7.37(1H，d，J＝8.5)，7.52(1H，d，J＝8.0)，7.67(1H，d，J＝7.5)，7.69(1H，d，J＝8.0)，7.86(1H，s)；
IR(KBr，cm -1)：3067，1678，1608，1497。
Embodiment 56
N-(4-(1-acetimidoyl piperidin-4-yl oxygen) phenyl)-N-(3-(3-carbamimido-phenyl)-2-fluoro-2-(Z)-propenyl) sulphonamide ethyl acetate dihydrochloride (exemplary compounds number: 1509)
(a) N-(3-(3-carbamimido-phenyl)-2-fluoro-2-(Z)-propenyl)-N-(4-(piperidin-4-yl oxygen) phenyl) sulphonamide ethyl acetate dihydrochloride
N-(4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen) phenyl)-N-(3-(3-cyano-phenyl)-2-fluoro-2-(Z)-propenyl) sulphonamide ethyl acetate (1.41g) is dissolved in the mixed solvent of methylene dichloride (25ml) and ethanol (25ml), passed into hydrogenchloride 1 hour under ice-cooled, the gained mixture at room temperature stirred in the reactor of jam-pack 10 hours.With the reaction mixture concentrating under reduced pressure, the gained residue is dissolved in the ethanol (30ml), adds aqueous ammonium chloride solution (0.25g is dissolved in the 10ml water) and 28% ammoniacal liquor (0.47ml), at room temperature places 8 hours.Add 4M hydrogenchloride dioxane solution (2.0ml), then steam solvent, residue HPLC (YMC-Pack ODS YMC, elutriant: 20% acetonitrile solution) refining, the gained amorphous solid is dissolved in the methyl alcohol (15ml), add 4M hydrogenchloride dioxane solution (0.5ml), then under reduced pressure be concentrated into driedly, obtain colourless amorphous solid title compound 1.00g (yield 75%).
1H?NMR(500MHz，DMSO-d 6)δppm：1.24(3H，t，J＝7.0)，1.81(2H，m)，2.08(2H，m)，3.06(2H，m)，3.22(2H，m)，4.20(2H，q，J＝7.0)，4.36(2H，s)，4.56(2H，d，J＝16.5)，4.65(1H，m)，5.94(1H，d，J＝39.0)，7.05(2H，d，J＝9.5)，7.40(2H，d，J＝9.5)，7.56(1H，d，J＝8.0)，7.74(2H，m)，7.81(1H，s)；
IR(KBr，cm -1)：3061，2985，1737，1676，1507。
(b) N-(4-(1-acetimidoyl piperidin-4-yl oxygen) phenyl)-N-(3-(3-carbamimido-phenyl)-2-fluoro-2-(Z)-propenyl) sulphonamide ethyl acetate dihydrochloride
N-(3-(3-carbamimido-phenyl)-2-fluoro-2-(Z)-propenyl)-N-(4-(piperidin-4-yl oxygen) phenyl) sulphonamide ethyl acetate dihydrochloride (800mg) is dissolved in the ethanol (20ml), add iminoester hydrochloride (515mg) and triethylamine (0.97ml), at room temperature stirred 4 hours.In reaction mixture, add 4M hydrogenchloride dioxane solution (2ml), then concentrating under reduced pressure, residue preparative HPLC (YMC-PackODS YMC, elutriant: 25% acetonitrile solution) refining, the gained amorphous solid is dissolved in the methyl alcohol (15ml), add 4M hydrogenchloride dioxane solution (0.5ml), then under reduced pressure be concentrated into driedly, obtain faint yellow amorphous solid title compound 458mg (yield 54%).
1H?NMR(500MHz，DMSO-d 6)δppm：1.24(3H，t，J＝7.0)，1.74(2H，m)，2.05(2H，m)，2.28(3H，s)，3.52(2H，m)，3.72(1H，m)，3.78(1H，m)，4.20(2H，q，J＝7.0)，4.36(2H，s)，4.59(2H，d，J＝15.5)，4.71(1H，m)，5.96(1H，d，J＝39.0)，7.05(2H，d，J＝9.5)，7.41(2H，d，J＝9.5)，7.59(1H，t，J＝7.5)，7.67(1H，d，J＝7.5)，7.76(1H，d，J＝7.5)，7.80(1H，s)；
IR(KBr，cm -1)：3103，1738，1673，1627，1606。
Embodiment 57
N-(4-(1-acetimidoyl piperidin-4-yl oxygen) phenyl)-N-(3-(3-carbamimido-phenyl)-2-fluoro-2-(Z)-propenyl) sulphonamide acetic acid dihydrochloride (exemplary compounds number: 2038)
N-(4-(1-acetimidoyl piperidin-4-yl oxygen) phenyl)-N-(3-(3-carbamimido-phenyl)-2-fluoro-2-(Z)-propenyl) sulphonamide ethyl acetate dihydrochloride (265mg) is dissolved in the 3M hydrochloric acid (15ml), stirs 2 hours at 80 ℃.Reaction mixture is cooled to reduce pressure after the room temperature and steams solvent, residue preparative HPLC (YMC-Pack ODS YMC, elutriant: 15% acetonitrile solution) refining, the gained amorphous solid is dissolved in the methyl alcohol (10ml), add 4M hydrogenchloride dioxane solution (0.2ml), then under reduced pressure be concentrated into dried.Residue is dissolved in the water (approximately 15ml), obtains colourless amorphous solid title compound 218mg (yield 86%) after lyophilize.
1H?NMR(500MHz，DMSO-d 6)δppm：1.74(2H，m)，2.05(2H，m)，2.29(3H，s)，3.52(2H，m)，3.72(1H，m)，3.82(1H，m)，4.20(2H，s)，4.59(2H，d，J＝15.5)，4.71(1H，m)，5.95(1H，d，J＝38.0)，7.06(2H，d，J＝9.0)，7.42(2H，d，J＝9.0)，7.59(1H，t，J＝8.0)，7.68(1H，d，J＝8.0)，7.76(1H，d，J＝8.0)，7.81(1H，s)；
IR(KBr，cm -1)：1734，1673，1627。
Embodiment 58
N-(4-(1-acetimidoyl piperidin-4-yl oxygen)-3,5-diamino formyl radical phenyl)-N-(3-(3-carbamimido-phenyl)-2-(E)-propenyl) sulphonamide ethyl acetate dihydrochloride (exemplary compounds number: 1506)
(a) N-(3-(3-carbamimido-phenyl)-2-(E)-propenyl)-N-(3,5-diamino formyl radical-4-(piperidin-4-yl oxygen) phenyl) sulphonamide ethyl acetate dihydrochloride
N-(4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-3; 5-diamino formyl radical phenyl)-N-(3-(3-cyano-phenyl)-2-(E)-propenyl) sulphonamide ethyl acetate (0.84g) is dissolved in the mixed solvent of methylene dichloride (25ml) and ethanol (25ml); passed into hydrogenchloride 1.5 hours under ice-cooled, the gained mixture at room temperature stirred in the reactor of jam-pack 3 hours.With the reaction mixture concentrating under reduced pressure, the gained residue is dissolved in the ethanol (25ml), adds aqueous ammonium chloride solution (0.15g is dissolved in the 5ml water) and 28% ammoniacal liquor (0.35ml), at room temperature stirs 2.5 hours, then places 12 hours.With the reaction mixture concentrating under reduced pressure, residue HPLC (YMC-Pack ODS YMC, elutriant: 17.5% acetonitrile solution) refining, the gained amorphous solid is dissolved in the ethanol (10ml), add 4M hydrogenchloride dioxane solution (0.20ml), then under reduced pressure be concentrated into driedly, obtain colourless amorphous solid title compound 0.17g (yield 20%).
1H?NMR(500MHz，DMSO-d 6)δppm：1.24(3H，t，J＝7.0)，1.85-2.00(4H，m)，2.95-3.05(2H，m)，3.20-3.30(2H，m)，4.20(2H，q，J＝7.0)，4.25-4.35(1H，m)，4.45(2H，s)，4.50(2H，d，J＝6.0)，6.45(1H，dt，J＝16.0，6.0)，6.61(1H，d，J＝16.0)，7.55(1H，t，J＝8.0)，7.61(2H，s)，7.67(1H，d，J＝8.0)，7.72(1H，d，J＝8.0)，7.88(1H，s)；
MASS(FAB，m/z)：587〔M+H]。
(b) N-(4-(1-acetimidoyl piperidin-4-yl oxygen)-3,5-diamino formyl radical phenyl)-N-(3-(3-carbamimido-phenyl)-2-(E)-propenyl) sulphonamide ethyl acetate dihydrochloride
N-(3-(3-carbamimido-phenyl)-2-(E)-propenyl)-N-(3; 5-diamino formyl radical-4-(piperidin-4-yl oxygen) phenyl) sulphonamide ethyl acetate dihydrochloride (0.17g) is dissolved in the ethanol (20ml); add iminoester hydrochloride (1.67g) and triethylamine (1.68ml), at room temperature stirred 5.5 hours.With the reaction mixture concentrating under reduced pressure, residue preparative HPLC (YMC-Pack ODS YMC, elutriant: 17% acetonitrile solution) refining, the gained amorphous solid is dissolved in the ethanol (5ml), add 4M hydrogenchloride dioxane solution (0.10ml), then under reduced pressure be concentrated into driedly, obtain colourless amorphous solid title compound 0.08g (yield 43%).
1H?NMR(500MHz，DMSO-d 6)δppm：1.24(3H，t，J＝7.0)，1.75-2.00(4H，m)，2.28(3H，s)，3.45-3.55(2H，m)，3.70-3.80(2H，m)，4.20(2H，q，J＝7.0)，4.30-4.40(1H，m)，4.45(2H，s)，4.51(2H，d，J＝6.0)，6.44(1H，dt，J＝16.0，6.0)，6.61(1H，d，J＝16.0)，7.55(1H，t，J＝8.0)，7.64(2H，s)，7.68(1H，d，J＝8.0)，7.72(1H，d，J＝8.0)，7.88(1H，s)；
MASS(FAB，m/z)：628[M+H]。
Embodiment 59
N-(4-(1-acetimidoyl piperidin-4-yl oxygen)-3,5-diamino formyl radical phenyl)-N-(3-(3-carbamimido-phenyl)-2-(E)-propenyl) sulphonamide acetic acid dihydrochloride (exemplary compounds number: 2035)
N-(4-(1-acetimidoyl piperidin-4-yl oxygen)-3; 5-diamino formyl radical phenyl)-and N-(3-(3-carbamimido-phenyl)-2-(E)-propenyl) sulphonamide ethyl acetate dihydrochloride (0.07g) is dissolved in the 3M hydrochloric acid (10ml), stirred 2 hours at 70 ℃.Reaction mixture carries out concentrating under reduced pressure after being cooled to room temperature, residue preparative HPLC (YMC-Pack ODS YMC, elutriant: 10% acetonitrile solution) refining, the gained amorphous solid is dissolved in the 1M hydrochloric acid (0.30ml), then under reduced pressure be concentrated into driedly, obtain colourless amorphous solid title compound 0.05g (yield 69%).
1H?NMR(500MHz，DMSO-d 6)δppm：1.75-2.00(4H，m)，2.27(3H，s)，3.45-3.55(2H，m)，3.70-3.80(2H，m)，4.32(2H，s)，4.35-4.40(1H，m)，4.51(2H，d，J＝6.0)，6.45(1H，dt，J＝16.0，6.0)，6.60(1H，d，J＝16.0)，7.55(1H，t，J＝8.0)，7.63(2H，s)，7.67(1H，d，J＝8.0)，7.72(1H，d，J＝8.0)，7.87(1H，s)；
IR(KBr，cm -1)：1729，1668。
Embodiment 60
N-(4-(1-acetimidoyl piperidin-4-yl oxygen)-5-formamyl-2-aminomethyl phenyl)-N-(3-(3-carbamimido-phenyl)-2-(E)-propenyl) sulphonamide ethyl acetate dihydrochloride (exemplary compounds number: 1491)
(a) N-(3-(3-carbamimido-phenyl)-2-(E)-propenyl)-N-(5-formamyl-2-methyl-4-(piperidin-4-yl oxygen) phenyl) sulphonamide ethyl acetate dihydrochloride
N-(4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-5-formamyl-2-aminomethyl phenyl)-N-(3-(3-cyano-phenyl)-2-(E)-propenyl) sulphonamide ethyl acetate (2.10g) is dissolved in the mixed solvent of methylene dichloride (25ml) and ethanol (25ml); passed into hydrogenchloride 1 hour under ice-cooled, the gained mixture at room temperature stirred in the reactor of jam-pack 3 hours.With the reaction mixture concentrating under reduced pressure, the gained residue is dissolved in the ethanol (25ml), add aqueous ammonium chloride solution (0.59g is dissolved in the 5ml water) and 28% ammoniacal liquor (1.34ml), reaction mixture at room temperature stirred 7 hours, then placed 12 hours.With the reaction mixture concentrating under reduced pressure, residue HPLC (YMC-Pack ODS YMC, elutriant: 17.5% acetonitrile solution) refining, the gained amorphous solid is dissolved in the ethanol (20ml), add 4M hydrogenchloride dioxane solution (1.40ml), then under reduced pressure be concentrated into driedly, obtain colourless amorphous solid title compound 1.18g (yield 57%).
1H?NMR(500MHz，DMSO-d 6)δppm：1.24(3H，t，J＝7.0)，1.85-1.95(2H，m)，2.10-2.20(2H，m)，2.33(3H，s)，3.05-3.15(2H，m)，3.20-3.30(2H，m)，4.21(2H，q，J＝7.0)，4.25-4.30(1H，m)，4.36(1H，d，J＝14.0)，4.45-4.50(1H，m)，4.51(1H，d，J＝14.0)，4.80(1H，m)，6.40-6.55(2H，m)，6.48(1H，s)，7.55(1H，t，J＝8.0)，7.69(1H，d，J＝8.0)，7.72(1H，d，J＝8.0)，7.77(1H，s)，7.83(1H，s)；
IR(KBr，cm -1)：1737，1673，1657。
(b) N-(4-(1-acetimidoyl piperidin-4-yl oxygen)-5-formamyl-2-aminomethyl phenyl)-N-(3-(3-carbamimido-phenyl)-2-(E)-propenyl) sulphonamide ethyl acetate dihydrochloride
N-(3-(3-carbamimido-phenyl)-2-(E)-propenyl)-N-(5-formamyl-2-methyl-4-(piperidin-4-yl oxygen) phenyl) sulphonamide ethyl acetate dihydrochloride (1.00g) is dissolved in the ethanol (50ml); add iminoester hydrochloride (0.59g) and triethylamine (1.33ml), at room temperature stir after 1 hour and placed 14 hours.With the reaction mixture concentrating under reduced pressure, residue preparative HPLC (YMC-Pack ODS YMC, elutriant: 20% acetonitrile solution) refining, the gained amorphous solid is dissolved in the ethanol (10ml), add 4M hydrogenchloride dioxane solution (1.00ml), then under reduced pressure be concentrated into driedly, obtain colourless amorphous solid title compound 0.98g (yield 92%).
1H?NMR(500MHz，DMSO-d 6)δppm：1.24(3H，t，J＝7.0)，1.75-1.90(2H，m)，2.00-2.15(2H，m)，2.30(3H，s)，2.34(3H，s)，3.50-3.60(2H，m)，3.70-3.80(1H，m)，3.80-3.90(1H，m)，4.21(2H，q，J＝7.0)，4.25-4.30(1H，m)，4.36(1H，d，J＝14.0)，4.45-4.50(1H，m)，4.51(1H，d，J＝14.0)，4.87(1H，m)，6.40-6.55(2H，m)，7.19(1H，s)，7.56(1H，t，J＝8.0)，7.70(1H，d，J＝8.0)，7.72(1H，d，J＝8.0)，7.82(1H，s)，7.84(1H，s)；
IR(KBr，cm -1)：1737，1672，1622。
Embodiment 61
N-(4-(1-acetimidoyl piperidin-4-yl oxygen)-5-formamyl-2-aminomethyl phenyl)-N-(3-(3-carbamimido-phenyl)-2-(E)-propenyl) sulphonamide acetic acid dihydrochloride (exemplary compounds number: 2020)
N-(4-(1-acetimidoyl piperidin-4-yl oxygen)-5-formamyl-2-aminomethyl phenyl)-N-(3-(3-carbamimido-phenyl)-2-(E)-propenyl) sulphonamide ethyl acetate dihydrochloride (0.80g) is dissolved in the 3M hydrochloric acid (40ml), stirs 1.5 hours at 70 ℃.Reaction mixture carries out concentrating under reduced pressure after being cooled to room temperature, residue preparative HPLC (YMC-Pack ODS YMC, elutriant: 12.5% acetonitrile solution) refining, the gained amorphous solid is dissolved in the 1M hydrochloric acid (3.00ml), then under reduced pressure be concentrated into driedly, obtain colourless amorphous solid title compound 0.71g (yield 92%).
1H?NMR(500MHz，DMSO-d 6)δppm：1.75-1.90(2H，m)，2.00-2.15(2H，m)，2.30(3H，s)，2.34(3H，s)，3.45-3.55(1H，m)，3.55-3.65(1H，m)，3.65-3.80(1H，m)，3.80-3.95(1H，m)，4.20-4.30(1H，m)，4.22(1H，d，J＝15.0)，4.41(1H，d，J＝15.0)，4.45-4.55(1H，m)，4.86(1H，m)，6.40-6.55(2H，m)，7.18(1H，s)，7.55(1H，t，J＝7.0)，7.70(1H，d，J＝7.0)，7.72(1H，d，J＝7.0)，7.83(1H，s)，7.84(1H，s)；
IR(KBr，cm -1)：1730，1672。
Reference example 1
3-cyano group phenylacrolein
3-cyanobenzaldehyde (4.5g) is dissolved in the toluene (200ml), adds the positive phosphorus subunit of triphenyl (phosphoranylidene) acetaldehyde (13.6g), then reaction mixture is stirred 4 hours at 70 ℃.With the reaction mixture concentrating under reduced pressure, refining (elutriant: methylene dichloride), recrystallization from the mixture of toluene and hexane again obtains the title compound 3.09g (yield 57%) of faint yellow needle crystal to residue with silica gel column chromatography.
1H?NMR(500MHz，CDCl 3)δppm：6.76(1H，dd，J＝16.0，7.5)，7.46(1H，d，J＝16.0)，7.58(1H，t，J＝8.0)，7.73(1H，d，J＝8.0)，7.80(1H，d，J＝8.0)，7.84(1H，s)，9.75(1H，d，J＝7.5)。
Reference example 2
3-(3-cyano-phenyl)-2-(E)-propylene-1-alcohol
3-cyano group phenylacrolein (3.00g) is dissolved in the mixed solvent of methylene dichloride (30ml) and ethanol (70ml), at ice-cooled lower adding sodium borohydride (1.32g) and Cerium II Chloride (2.49g), then under same temperature, stirred 1.5 hours.In reaction mixture, add saturated aqueous ammonium chloride, use dichloromethane extraction 3 times, extraction liquid saturated common salt water washing, organic layer anhydrous sodium sulfate drying.Decompression steams solvent, and residue is made with extra care (elutriant: hexane/ethyl acetate=3/2), obtain the title compound 3.27g (quantitative yield) of faint yellow oily with silica gel column chromatography.
1H?NMR(500MHz，CDCl 3)δppm：4.37(2H，m)，6.43(1H，dt，J＝16.0，5.0)，6.62(1H，d，J＝16.0)，7.43(1H，t，J＝8.0)，7.52(1H，d，J＝8.0)，7.60(1H，d，J＝8.0)，7.65(1H，s)。
Reference example 3
Carbonic acid (3-(3-cyano-phenyl)-2-(E)-propenyl) ethyl ester
3-(3-cyano-phenyl)-2-(E)-propylene-1-alcohol (403mg) is dissolved in the methylene dichloride (6ml), add pyridine (1ml), then at ice-cooled lower dropping Vinyl chloroformate (0.38ml), under same temperature, stirred 2 hours.In reaction mixture, add aqueous ammonium chloride solution, then use ethyl acetate extraction, extraction liquid water and saturated common salt water washing, the organic layer anhydrous sodium sulfate drying, decompression steams solvent after filtering, residue is made with extra care (elutriant: hexane/ethyl acetate=4/1), obtain the title compound 492mg (yield 84%) of colorless oil with silica gel column chromatography.
1H?NMR(500MHz，CDC1 3)δppm：1.34(3H，t，J＝7.0)，4.24(2H，q，J＝7.0)，4.80(2H，d，J＝5.5)，6.36(1H，dt，J＝16.0，5.5)，6.67(1H，d，J＝16.0)，7.44(1H，t，J＝8.0)，7.55(1H，d，J＝8.0)，7.61(1H，d，J＝8.0)，7.66(1H，s)。
Reference example 4
4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen) oil of mirbane
Sodium hydride (2.2g) is suspended in the N,N-dimethylacetamide (150ml) after cleaning with hexane, at ice-cooled lower adding 1-tertbutyloxycarbonyl-4-hydroxy piperidine (10.1g), then stirs 2 hours under same temperature.Subsequently, in reaction mixture, add the 4-fluoronitrobenzene with 20 minutes, the burgundy reaction soln was stirred 4 hours.Add saturated aqueous ammonium chloride in the reaction mixture and make reaction terminating.Then with methyl tertiary butyl ether extraction 3 times, extraction liquid water and saturated common salt water washing, organic layer anhydrous sodium sulfate drying.Decompression steams solvent, and residue is made with extra care (elutriant: hexane/ethyl acetate=2/1), obtain faint yellow solid title compound 11.9g (yield 74%) with silica gel column chromatography.
1H?NMR(400MHz，CDCl 3)δppm：1.43(9H，s)，1.76(2H，m)，1.91(2H，m)，3.34(2H，m)，3.65(2H，m)，4.56(1H，m)，6.91(2H，d，J＝9.0)，8.15(2H，d，J＝9.0)。
Reference example 5
4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen) aniline
4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen) oil of mirbane (11.9g) is dissolved in the methyl alcohol (100ml), adds palladium carbon catalyzer (1.9g), then at room temperature stirs in atmosphere of hydrogen 4 hours.Reaction mixture is filtered, and filtrate decompression is concentrated, and residue is made with extra care (elutriant: hexane/ethyl acetate=1/1), obtain incarnadine solid title compound 10.7g (yield 99%) with silica gel column chromatography.
1H?NMR(400MHz，CDCl 3)δppm：1.46(9H，s)，1.71(2H，m)，1.87(2H，m)，3.27(2H，m)，3.71(2H，m)，4.26(1H，m)，6.63(2H，d，J＝8.5)，6.76(2H，d，J＝8.5)。
Reference example 6
N-(4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen) phenyl) ethyl sulfonamide
4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen) aniline (10.6g) and pyridine (8ml) are dissolved in the methylene dichloride (75ml), at ice-cooled lower dropping ethyl sulfonyl chloride (4.1ml), then at room temperature stir 5 hours.In reaction mixture, add methyl alcohol (1ml), concentrating under reduced pressure then, residue is with the refining (elutriant: hexane/ethyl acetate=3/2), obtain pink solid title compound 11.7g (yield 84%) of silica gel column chromatography.
1H?NMR(400MHz，CDC1 3)δppm：1.38(3H，t，J＝8.0)，1.47(9H，s)，1.74(2H，m)，1.90(2H，m)，3.07(2H，q，J＝8.0)，3.34(2H，m)，3.69(2H，m)，4.42(1H，m)，6.88(2H，d，J＝9.0)，7.17(2H，d，J＝9.0)。
Reference example 7
N-(4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen) phenyl)-N-(3-(3-cyano-phenyl)-2-(E)-propenyl) ethyl sulfonamide
Carbonic acid (3-(3-cyano-phenyl)-2-(E)-propenyl) ethyl ester (1.04g) and N-(4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen) phenyl) ethyl sulfonamide (1.15g) is suspended in the tetrahydrofuran (THF) (9ml), add three (dibenzalacetone) palladium chloroform complex (0.077g) and triphenylphosphine (0.039g), then at room temperature stirred 3 hours.With the reaction mixture concentrating under reduced pressure, residue is made with extra care (elutriant: dichloromethane/ethyl acetate=8/1), obtain faint yellow oily title compound 1.57g (quantitative yield) with silica gel column chromatography.
1H?NMR(500MHz，CDCl 3)δppm：1.42(3H，t，J＝7.0)，1.47(9H，s)，1.74(2H，m)，1.90(2H，m)，3.06(2H，q，J＝7.0)，3.34(2H，m)，3.68(2H，m)，4.42(2H，d，J＝7.0)，4.44(1H，m)，6.28(1H，dt，J＝15.5，7.0)，6.42(1H，d，J＝15.5)，6.89(2H，d，J＝9.0)，7.26(2H，d，J＝9.0)，7.40(1H，t，J＝7.5)，7.52(2H，m)，7.56(1H，s)。
Reference example 8
3-(3-cyano-phenyl)-2-methyl-2-(E)-propenal
3-cyanobenzaldehyde (2.62g) is dissolved in the toluene (90ml), adds the inferior positive phosphorus base propionic aldehyde (8.28g) of 2-triphenyl, then reaction mixture is stirred 11 hours at 70 ℃.With the reaction mixture concentrating under reduced pressure, refining (elutriant: methylene dichloride), recrystallization from the mixture of toluene and hexane again obtains the title compound 2.61g (yield 76%) of faint yellow needle crystal to residue with silica gel column chromatography.
1H?NMR(500MHz，CDCl 3)δppm：2.07(3H，s)，7.25(1H，bs)，7.59(1H，t，J＝8.0)，7.68(1H，d，J＝8.0)，7.74(1H，d，J＝8.0)，7.79(1H，s)，9.63(1H，s)。
Reference example 9
3-(3-cyano-phenyl)-2-methyl-2-(E)-propylene-1-alcohol
3-(3-cyano-phenyl)-2-methyl-2-(E)-propenal (2.00g) is dissolved in the mixed solvent of methylene dichloride (30ml) and ethanol (60ml), at ice-cooled lower adding sodium borohydride (0.83g) and Cerium II Chloride (1.30g), then under same temperature, stirred 1.5 hours.In reaction mixture, add saturated aqueous ammonium chloride, use dichloromethane extraction 3 times, extraction liquid saturated common salt water washing, organic layer anhydrous sodium sulfate drying.Decompression steams solvent after filtering, and residue is made with extra care (elutriant: hexane/ethyl acetate=1/1), obtain the title compound 2.05g (quantitative yield) of faint yellow oily with silica gel column chromatography.
1H?NMR(500MHz，CDCl 3)δppm：1.87(3H，s)，4.22(2H，m)，6.52(1H，bs)，7.42-7.52(3H，m)，7.55(1H，s)。
Reference example 10
Carbonic acid (3-(3-cyano-phenyl)-2-methyl-2-(E)-propenyl) ethyl ester
3-(3-cyano-phenyl)-2-methyl-2-(E)-propylene-1-alcohol (2.00g) is dissolved in the methylene dichloride (20ml), add pyridine (3ml), then at ice-cooled lower dropping Vinyl chloroformate (1.30ml), at room temperature stirred 12 hours.With the reaction mixture concentrating under reduced pressure, residue is made with extra care (elutriant: hexane/ethyl acetate=4/1), obtain colorless oil title compound 2.46g (yield 87%) with silica gel column chromatography.
1H?NMR(400MHz，CDCl 3)δppm：1.34(3H，t，J＝7.0)，1.90(3H，s)，4.25(2H，q，J＝7.0)，4.70(2H，s)，6.53(1H，bs)，7.43-7.55(4H，m)。
Reference example 11
N-(4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen) phenyl)-N-(3-(3-cyano-phenyl)-2-methyl-2-(E)-propenyl) ethyl sulfonamide
Carbonic acid (3-(3-cyano-phenyl)-2-methyl-2-(E)-propenyl) ethyl ester (1.10g) and N-(4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen) phenyl) ethyl sulfonamide (1.15g) is suspended in the tetrahydrofuran (THF) (9ml), add three (dibenzalacetone) palladium chloroform complex (78mg) and triphenylphosphine (39mg), then at room temperature stirred 16 hours.With the reaction mixture concentrating under reduced pressure, residue is made with extra care (elutriant: dichloromethane/ethyl acetate=12/1), obtain colourless amorphous solid title compound 0.58g (yield 36%) with silica gel column chromatography.
1H?NMR(500MHz，CDCl 3)δppm：1.42(3H，t，J＝7.5)，1.47(9H，s)，1.75(2H，m)，1.89(3H，s)，1.91(2H，m)，3.07(2H，q，J＝7.5)，3.34(2H，m)，3.69(2H，m)，4.37(2H，s)，4.45(1H，m)，6.21(1H，s)，6.89(2H，d，J＝9.0)，7.26(2H，d，J＝9.0)，7.32(1H，d，J＝8.0)，7.35(1H，s)，7.38(1H，t，J＝8.0)，7.48(1H，d，J＝8.0)。
Reference example 12
N-(4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen) phenyl) sulphonamide ethyl acetate
4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen) aniline (4.39g) and pyridine (2.4ml) are dissolved in the methylene dichloride (30ml), in ice-cooled lower dropping chlorine sulphonyl ethyl acetate (2.4ml), then at room temperature stirring 13 hours.In reaction mixture, add methyl alcohol (0.5ml), concentrating under reduced pressure then, residue is with the refining (elutriant: hexane/ethyl acetate=3/2), obtain incarnadine oily title compound 4.96g (yield 75%) of silica gel column chromatography.
1H?NMR(400MHz，CDCl 3)δppm：1.33(3H，t，J＝7.0)，1.47(9H，s)，1.75(2H，m)，1.90(2H，m)，3.34(2H，m)，3.69(2H，m)，3.89(2H，s)，4.29(2H，q，J＝7.0)，4.44(1H，m)，6.89(2H，d，J＝8.5)，7.27(2H，d，J＝8.5)。
Reference example 13
N-(4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen) phenyl)-N-(3-(3-cyano-phenyl)-2-(E)-propenyl) sulphonamide ethyl acetate
3-(3-cyano-phenyl)-2-(E)-propylene-1-alcohol (0.80g), N-(4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen) phenyl) sulphonamide ethyl acetate (2.21g) and triphenylphosphine (1.70g) are dissolved in the methylene dichloride (40ml), at ice-cooled lower dropping diethyl azodiformate (1.0ml), then under same temperature, stirred 2 hours.With the reaction mixture concentrating under reduced pressure, residue is made with extra care (elutriant: dichloromethane/ethyl acetate=10/1), obtain colorless oil title compound 2.15g (yield 74%) with silica gel column chromatography.
1H?NMR(500MHz，CDC1 3)δppm：1.35(3H，t，J＝7.0)，1.47(9H，s)，1.75(2H，m)，1.90(2H，m)，3.34(2H，m)，3.68(2H，m)，3.98(2H，s)，4.30(2H，q，J＝7.0)，4.45(1H，m)，4.47(2H，d，J＝6.0)，6.24(1H，dt，J＝15.5，6.0)，6.40(1H，d，J＝15.5)，6.90(2H，d，J＝8.5)，7.39(3H，m)，7.51(2H，m)，7.55(1H，s)。
Reference example 14
4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-2-methyl oil of mirbane
1-tertbutyloxycarbonyl-4-hydroxy piperidine (6.04g), 3-methyl-4-nitrophenols (4.59g) and triphenylphosphine (10.20g) are dissolved in the methylene dichloride (100ml), at ice-cooled lower dropping diethyl azodiformate (6.1ml), then at room temperature stirred 6 hours.With the reaction mixture concentrating under reduced pressure, residue is made with extra care (elutriant: hexane/ethyl acetate=3/1), obtain faint yellow solid title compound 6.04g (yield 60%) with silica gel column chromatography.
1H?NMR(400MHz，CDC1 3)δppm：1.48(9H，s)，1.78(2H，m)，1.94(2H，m)，2.62(3H，s)，3.38(2H，m)，3.69(2H，m)，4.58(1H，m)，6.80(2H，m)，8.08(1H，d，J＝9.5)。
Reference example 15
4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-2-aminotoluene
4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-2-methyl oil of mirbane (3.23g) is dissolved in the methyl alcohol (30ml), adds palladium carbon catalyzer (0.21g), then at room temperature stirs in atmosphere of hydrogen 4 hours.Reaction mixture is filtered, and filtrate decompression is concentrated, and residue is made with extra care (elutriant: hexane/ethyl acetate=1/1), obtain incarnadine oily title compound 3.02g (yield 99%) with silica gel column chromatography.
1H?NMR(400MHz，CDCl 3)δppm：1.47(9H，s)，1.70(2H，m)，1.87(2H，m)，2.12(3H，s)，3.27(2H，m)，3.71(2H，m)，4.26(1H，m)，6.59-6.69(3H，m)。
Reference example 16
N-(4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-2-aminomethyl phenyl) sulphonamide ethyl acetate
4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-2-aminotoluene (3.00g) and pyridine (1.6ml) are dissolved in the methylene dichloride (20ml), in ice-cooled lower dropping chlorine sulphonyl ethyl acetate (1.6ml), then at room temperature stirring 13 hours.In reaction mixture, add methyl alcohol (1ml), concentrating under reduced pressure then, residue is with the refining (elutriant: hexane/ethyl acetate=3/2), obtain faint yellow solid title compound 2.35g (yield 53%) of silica gel column chromatography.
1H?NMR(500MHz，CDC1 3)δppm：1.33(3H，t，J＝7.0)，1.47(9H，s)，1.74(2H，m)，1.90(2H，m)，2.38(3H，s)，3.34(2H，m)，3.68(2H，m)，4.01(2H，s)，4.29(2H，q，J＝7.0)，4.43(1H，m)，6.73(1H，dd，J＝8.5，3.0)，6.80(1H，d，J＝3.0)，7.34(1H，d，J＝8.0)。
Reference example 17
N-(4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-2-aminomethyl phenyl)-N-(3-(3-cyano-phenyl)-2-(E)-propenyl) sulphonamide ethyl acetate
3-(3-cyano-phenyl)-2-(E)-propylene-1-alcohol (0.48g), N-(4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-2-aminomethyl phenyl) sulphonamide ethyl acetate (1.37g) and triphenylphosphine (0.94g) are dissolved in the methylene dichloride (20ml), at ice-cooled lower dropping diethyl azodiformate (0.57ml), then under same temperature, stirred 2 hours.With the reaction mixture concentrating under reduced pressure, residue is made with extra care (elutriant: dichloromethane/ethyl acetate=11/1), obtain faint yellow amorphous solid title compound 1.80g (quantitative yield) with silica gel column chromatography.
1H?NMR(500MHz，CDCl 3)δppm：1.36(3H，t，J＝7.0)，1.47(9H，s)，1.74(2H，m)，1.90(2H，m)，2.35(3H，s)，3.34(2H，m)，3.68(2H，m)，3.99(1H，d，J＝15.0)，4.12(1H，d，J＝15.0)，4.27(1H，dd，J＝15.0，6.0)，4.31(2H，m)，4.44(1H，m)，4.50(1H，dd，J＝15.0，6.0)，6.28(1H，dt，J＝16.5，6.0)，6.32(1H，d，J＝16.5)，6.76(1H，dd，J＝9.0，3.0)，6.79(1H，d，J＝3.0)，7.39(1H，d，J＝9.0)，7.41(1H，d，J＝7.5)，7.52(3H，m)。
Reference example 18
4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-3-methoxy nitrobenzene
1-tertbutyloxycarbonyl-4-hydroxy piperidine (3.02g), 2-methoxyl group-4-nitrophenols (2.54g) and triphenylphosphine (10.20g) are dissolved in the methylene dichloride (60ml), at ice-cooled lower dropping diethyl azodiformate (3.1ml), then at room temperature stirred 20 hours.With the reaction mixture concentrating under reduced pressure, residue is made with extra care (elutriant: hexane/ethyl acetate=5/2), obtain faint yellow oily title compound 4.36g (yield 82%) with silica gel column chromatography.
1H?NMR(500MHz，CDCl 3)δppm：1.47(9H，s)，1.83(2H，m)，1.96(2H，m)，3.33(2H，m)，3.77(2H，m)，3.94(3H，s)，4.61(1H，m)，6.94(1H，d，J＝9.0)，7.76(1H，d，J＝2.0)，7.87(1H，dd，J＝9.0，2.0)。
Reference example 19
4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-3-anisidine
4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-3-methoxy nitrobenzene (4.36g) is dissolved in the methyl alcohol (60ml), adds palladium carbon catalyzer (0.25g), then at room temperature stirs in atmosphere of hydrogen 65 hours.Reaction mixture is filtered, and filtrate decompression is concentrated, and residue is made with extra care (elutriant: hexane/ethyl acetate=1/1), obtain incarnadine oily title compound 2.03g (yield 51%) with silica gel column chromatography.
1H?NMR(500MHz，CDCl 3)δppm：1.46(9H，s)，1.71(2H，m)，1.87(2H，m)，3.18(2H，m)，3.78(2H，m)，3.80(3H，s)，4.15(1H，m)，6.19(1H，dd，J＝8.5，3.0)，6.29(1H，d，J＝3.0)，6.76(1H，d，J＝8.5)。
Reference example 20
N-(4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-3-p-methoxy-phenyl) sulphonamide ethyl acetate
4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-3-anisidine (2.00g) and pyridine (1.0ml) are dissolved in the methylene dichloride (40ml), in ice-cooled lower dropping chlorine sulphonyl ethyl acetate (1.0ml), under same temperature, stirred 2 hours, continue again at room temperature to stir 5 hours.With the reaction mixture concentrating under reduced pressure, residue is made with extra care (elutriant: hexane/ethyl acetate=2/1), obtain incarnadine oily title compound 2.56g (yield 87%) with silica gel column chromatography.
1H?NMR(500MHz，CDCl 3)δppm：1.32(3H，t，J＝7.0)，1.47(9H，s)，1.76(2H，m)，1.90(2H，m)，3.25(2H，m)，3.78(2H，m)，3.85(3H，s)，3.92(2H，s)，4.29(2H，q，J＝7.0)，4.36(1H，m)，6.82(1H，dd，J＝9.0，2.5)，6.88(1H，d，J＝9.0)，6.96(1H，d，J＝2.5)。
Reference example 21
N-(4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-3-p-methoxy-phenyl)-N-(3-(3-cyano-phenyl)-2-(E)-propenyl) sulphonamide ethyl acetate
3-(3-cyano-phenyl)-2-(E)-propylene-1-alcohol (338mg), N-(4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-3-p-methoxy-phenyl) sulphonamide ethyl acetate (823mg) and triphenylphosphine (1000mg) are dissolved in the methylene dichloride (20ml), at ice-cooled lower dropping diethyl azodiformate (0.43ml), then under same temperature, stirred 1 hour.With the reaction mixture concentrating under reduced pressure, residue is made with extra care (elutriant: hexane/ethyl acetate=12/1), obtain colourless amorphous solid title compound 985mg (yield 76%) with silica gel column chromatography.
1H?NMR(500MHz，CDCl 3)δppm：1.37(3H，t，J＝7.0)，1.48(9H，s)，1.78(2H，m)，1.93(2H，m)，3.27(2H，m)，3.80(2H，m)，3.84(3H，s)，4.02(2H，s)，4.32(2H，q，J＝7.0)，4.43(1H，m)，4.50(2H，d，J＝7.0)，6.27(1H，dt，J＝15.5，7.0)，6.42(1H，d，J＝15.5)，6.92(1H，d，J＝8.0)，7.03(1H，dd，J＝8.0，3.0)，7.05(1H，d，J＝3.0)，7.42(1H，t，J＝8.0)，7.53(2H，m)，7.58(1H，s)。
Reference example 22
4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-3-fluoronitrobenzene
1-tertbutyloxycarbonyl-4-hydroxy piperidine (3.02g), 2-fluoro-4-nitrophenol (2.36g) and triphenylphosphine (5.11g) are dissolved in the methylene dichloride (60ml), at ice-cooled lower dropping diethyl azodiformate (3.1ml), then at room temperature stirred 14 hours.With the reaction mixture concentrating under reduced pressure, residue is made with extra care (elutriant: hexane/ethyl acetate=5/2), obtain faint yellow solid title compound 3.71g (yield 73%) with silica gel column chromatography.
1H?NMR(500MHz，CDC1 3)δppm：1.48(9H，s)，1.84(2H，m)，1.97(2H，m)，3.41(2H，m)，3.71(2H，m)，4.66(1H，m)，7.05(1H，m)，8.04(2H，m)。
Reference example 23
4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-3-fluoroaniline
4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-3-fluoronitrobenzene (3.71g) is dissolved in the methyl alcohol (50ml), adds palladium carbon catalyzer (0.30g), then at room temperature stirs in atmosphere of hydrogen 4 hours.Reaction mixture is filtered, and filtrate decompression is concentrated, and residue is made with extra care (elutriant: hexane/ethyl acetate=1/1), obtain incarnadine solid title compound 3.27g (yield 97%) with silica gel column chromatography.
1H?NMR(500MHz，CDCl 3)δppm：1.46(9H，s)，1.72(2H，m)，1.86(2H，m)，3.23(2H，m)，3.75(2H，m)，4.17(1H，m)，6.35(1H，dd，J＝8.5，3.0)，6.44(1H，dd，J＝12.5，3.0)，6.82(1H，dd，J＝9.0，8.5)。
Reference example 24
N-(4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-3-fluorophenyl) sulphonamide ethyl acetate
4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-3-fluoroaniline (1.49g) and pyridine (0.77ml) are dissolved in the methylene dichloride (30ml), in ice-cooled lower dropping chlorine sulphonyl ethyl acetate (0.77ml), then at room temperature stirred 7 hours.With the reaction mixture concentrating under reduced pressure, residue is made with extra care (elutriant: hexane/ethyl acetate=3/2), obtain incarnadine oily title compound 1.58g (yield 71%) with silica gel column chromatography.
1H?NMR(500MHz，CDCl 3)δppm：1.33(3H，t，J＝7.0)，1.47(9H，s)，1.77(2H，m)，1.90(2H，m)，3.32(2H，m)，3.72(2H，m)，3.92(2H，s)，4.29(2H，q，J＝7.0)，4.42(1H，m)，6.97(1H，dd，J＝9.0，8.5)，7.04(1H，dd，J＝9.0，3.0)，7.17(1H，dd，J＝11.5，3.0)。
Reference example 25
N-(4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-3-fluorophenyl)-N-(3-(3-cyano-phenyl)-2-(E)-propenyl) sulphonamide ethyl acetate
3-(3-cyano-phenyl)-2-(E)-propylene-1-alcohol (0.40g), N-(4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-3-fluorophenyl) sulphonamide ethyl acetate (1.15g) and triphenylphosphine (0.85g) are dissolved in the methylene dichloride (20ml), at ice-cooled lower dropping diethyl azodiformate (0.51ml), under same temperature, stirred 3 hours.With the reaction mixture concentrating under reduced pressure, residue is made with extra care (elutriant: dichloromethane/ethyl acetate=10/1), obtain faint yellow amorphous solid title compound 1.21g (yield 81%) with silica gel column chromatography.
1H?NMR(500MHz，CDCl 3)δppm：1.35(3H，t，J＝7.0)，1.47(9H，s)，1.77(2H，m)，1.91(2H，m)，3.34(2H，m)，3.70(2H，m)，3.98(2H，s)，4.31(2H，q，J＝7.0)，4.46(1H，m)，4.47(2H，d，J＝7.0)，6.22(1H，dt，J＝16.0，7.0)，6.41(1H，d，J＝16.0)，6.98(1H，dd，J＝9.0，8.5)，7.20(1H，dd，J＝8.5，2.0)，7.27(1H，m)，7.40(1H，dd，J＝8.0，7.0)，7.52(1H，d，J＝7.0)，7.53(1H，d，J＝8.0)，7.56(1H，s)。
Reference example 26
4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-3-chloronitrobenzene
1-tertbutyloxycarbonyl-4-hydroxy piperidine (3.32g), 2-chloro-4-nitrophenols (2.36g) and triphenylphosphine (5.11g) are dissolved in the methylene dichloride (60ml), at ice-cooled lower dropping diethyl azodiformate (3.1ml), then at room temperature stirred 18 hours.With the reaction mixture concentrating under reduced pressure, residue is made with extra care (elutriant: hexane/ethyl acetate=5/2), obtain faint yellow solid title compound 3.90g (yield 76%) with silica gel column chromatography.
1H?NMR(500MHz，CDCl 3)δppm：1.48(9H，s)，1.84-1.98(4H，m)，3.54(2H，m)，3.62(2H，m)，4.73(1H，m)，7.00(1H，d，J＝9.0)，8.14(1H，dd，J＝9.0，3.0)，8.31(1H，d，J＝3.0)。
Reference example 27
4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-3-chloroaniline
4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-3-chloronitrobenzene (2.40g) is dissolved in the acetic acid (50ml), at room temperature divides 4 times and adds zinc powder (5.60g), then stirs 2 hours.Reaction mixture is filtered, and filtrate decompression is concentrated, and residue is made with extra care (elutriant: hexane/ethyl acetate=1/1), obtain orange oily title compound 1.99g (yield 87%) with silica gel column chromatography.
1H?NMR(500MHz，CDCl 3)δppm：1.47(9H，s)，1.77(2H，m)，1.87(2H，m)，3.31(2H，m)，3.72(2H，m)，4.26(1H，m)，6.52(1H，dd，J＝9.0，3.0)，6.73(1H，d，J＝3.0)，6.80(1H，d，J＝9.0)。
Reference example 28
N-(4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-3-chloro-phenyl-) sulphonamide ethyl acetate
4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-3-chloroaniline (1.50g) and pyridine (0.56ml) are dissolved in the methylene dichloride (20ml), in ice-cooled lower dropping chlorine sulphonyl ethyl acetate (0.74ml), then at room temperature stirred 5 hours.With the reaction mixture concentrating under reduced pressure, residue is made with extra care (elutriant: hexane/ethyl acetate=3/2), obtain incarnadine oily title compound 1.19g (yield 54%) with silica gel column chromatography.
1H?NMR(500MHz，CDCl 3)δppm：1.34(3H，t，J＝7.0)，1.47(9H，s)，1.79-1.92(4H，m)，3.46(2H，m)，3.64(2H，m)，3.92(2H，s)，4.30(2H，q，J＝7.0)，4.52(1H，m)，6.94(1H，d，J＝9.0)，7.22(1H，dd，J＝9.0，2.5)，7.40(1H，d，J＝2.5)。
Reference example 29
N-(4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-3-chloro-phenyl-)-N-(3-(3-cyano-phenyl)-2-(E)-propenyl) sulphonamide ethyl acetate
3-(3-cyano-phenyl)-2-(E)-propylene-1-alcohol (0.40g), N-(4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-3-chloro-phenyl-) sulphonamide ethyl acetate (1.19g) and triphenylphosphine (0.79g) are dissolved in the methylene dichloride (20ml), at ice-cooled lower dropping diethyl azodiformate (0.50ml), under same temperature, stirred 2.5 hours.With the reaction mixture concentrating under reduced pressure, residue is made with extra care (elutriant: dichloromethane/ethyl acetate=10/1), obtain incarnadine amorphous solid title compound 1.20g (yield 78%) with silica gel column chromatography.
1H?NMR(500MHz，CDC1 3)δppm：1.36(3H，t，J＝7.0)，1.47(9H，s)，1.79-1.92(4H，m)，3.47(2H，m)，3.62(2H，m)，3.99(2H，s)，4.31(2H，q，J＝7.0)，4.47(2H，d，J＝6.5)，4.55(1H，m)，6.23(1H，dt，J＝16.0，6.5)，6.41(1H，d，J＝16.0)，6.94(1H，d，J＝9.0)，7.32(1H，dd，J＝9.0，3.0)，7.41(1H，t，J＝7.5)，7.50-7.58(4H，m)。
Reference example 30
4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-3-trifluoromethyl nitrobenzene
1-tertbutyloxycarbonyl-4-hydroxy piperidine (1.45g), 2-trifluoromethyl-4-nitrophenols (1.38g) are (according to the organic chemistry magazine, 63,4199 (1998) described methods are from 3-trifluoromethyl nitrobenzene preparation) and triphenylphosphine (2.27g) be dissolved in the methylene dichloride (65ml), at ice-cooled lower dropping diethyl azodiformate (1.4ml), then at room temperature stirred 24 hours.With the reaction mixture concentrating under reduced pressure, residue is made with extra care (elutriant: methylene dichloride), obtain faint yellow oily title compound 2.28g (yield 88%) with silica gel column chromatography.
1H?NMR(500MHz，CDCl 3)δppm：1.49(9H，s)，1.88-1.99(4H，m)，3.51(2H，m)，3.64(2H，m)，4.83(1H，m)，7.09(1H，d，J＝9.0)，8.41(1H，dd，J＝9.0，3.0)，8.53(1H，d，J＝3.0)。
Reference example 31
4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-3-5-trifluoromethylaniline
4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-3-trifluoromethyl nitrobenzene (2.28g) is dissolved in the methyl alcohol (50ml), adds palladium carbon catalyzer (0.20g), then at room temperature stirs in atmosphere of hydrogen 5 hours.Reaction mixture is filtered, and filtrate decompression is concentrated, and residue is made with extra care (elutriant: hexane/ethyl acetate=3/2), obtain incarnadine oily title compound 1.69g (yield 80%) with silica gel column chromatography.
1H?NMR(500MHz，CDCl 3)δppm：1.47(9H，s)，1.76-1.88(4H，m)，3.43(2H，m)，3.59(2H，m)，4.46(1H，m)，6.78(1H，dd，J＝9.0，3.0)，6.83(1H，d，J＝9.0)，6.91(1H，d，J＝3.0)。
Reference example 32
N-(4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-3-trifluoromethyl) sulphonamide ethyl acetate
4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-3-5-trifluoromethylaniline (1.69g) and pyridine (0.49ml) are dissolved in the methylene dichloride (20ml), in ice-cooled lower dropping chlorine sulphonyl ethyl acetate (0.76ml), then at room temperature stirred 3 hours.With the reaction mixture concentrating under reduced pressure, residue is made with extra care (elutriant: hexane/ethyl acetate=3/2), obtain incarnadine oily title compound 1.74g (yield 73%) with silica gel column chromatography.
1H?NMR(500MHz，CDCl 3)δppm：1.34(3H，t，J＝7.0)，1.48(9H，s)，1.83-1.94(4H，m)，3.48-3.60(4H，m)，3.91(2H，s)，4.31(2H，q，J＝7.0)，4.65(1H，m)，6.99(1H，d，J＝9.0)，7.52(1H，dd，J＝9.0，2.5)，7.56(1H，d，J＝2.5)。
Reference example 33
N-(4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-3-trifluoromethyl)-N-(3-(3-cyano-phenyl)-2-(E)-propenyl) sulphonamide ethyl acetate
3-(3-cyano-phenyl)-2-(E)-propylene-1-alcohol (0.57g), N-(4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-3-trifluoromethyl) sulphonamide ethyl acetate (1.74g) and triphenylphosphine (1.07g) are dissolved in the methylene dichloride (27ml), at ice-cooled lower dropping diethyl azodiformate (0.65ml), under same temperature, stirred 3 hours.With the reaction mixture concentrating under reduced pressure, residue is made with extra care (elutriant: dichloromethane/ethyl acetate=12/1), obtain colourless amorphous solid title compound 2.06g (yield 93%) with silica gel column chromatography.
1H?NMR(500MHz，CDCl 3)δppm：1.35(3H，t，J＝7.0)，1.47(9H，s)，1.82-1.92(4H，m)，3.46-3.62(4H，m)，3.98(2H，s)，4.31(2H，q，J＝7.0)，4.48(2H，d，J＝6.5)，4.66(1H，m)，6.22(1H，dt，J＝16.0，6.5)，6.41(1H，d，J＝16.0)，6.98(1H，d，J＝7.5)，7.41(1H，dd，J＝8.0，7.5)，7.52(2H，m)，7.57(1H，s)，7.58(1H，dd，J＝9.0，2.0)，7.72(1H，d，J＝2.0)。
Reference example 34
4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-3-methyl oil of mirbane
1-tertbutyloxycarbonyl-4-hydroxy piperidine (3.62g), 2-methyl-4-nitrophenols (2.55g) and triphenylphosphine (5.25g) are dissolved in the methylene dichloride (100ml), at ice-cooled lower dropping diethyl azodiformate (3.2ml), then at room temperature stirred 18 hours.With the reaction mixture concentrating under reduced pressure, residue is made with extra care (elutriant: methylene dichloride), obtain the thick title compound 4.07g of faint yellow oily with silica gel column chromatography.
1H?NMR(500MHz，CDCl 3)δppm：1.48(9H，s)，1.84(2H，m)，1.95(2H，m)，2.29(3H，s)，3.49(2H，m)，3.62(2H，m)，4.66(1H，m)，6.86(1H，d，J＝8.5)，8.07(2H，m)。
Reference example 35
4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-3-monomethylaniline
4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-3-methyl oil of mirbane (4.07g) is dissolved in the methyl alcohol (40ml), adds palladium carbon catalyzer (0.41g), then at room temperature stirs in atmosphere of hydrogen 4 hours.Reaction mixture is filtered, and filtrate decompression is concentrated, and residue is made with extra care (elutriant: hexane/ethyl acetate=3/2), obtain incarnadine oily title compound 2.73g (2 step yields 53% of reference example 41) with silica gel column chromatography.
1H?NMR(500MHz，CDCl 3)δppm：1.47(9H，s)，1.74(2H，m)，1.87(2H，m)，2.17(3H，s)，3.30(2H，m)，3.68(2H，m)，4.25(1H，m)，6.47(1H，dd，J＝8.5，2.5)，6.53(1H，d，J＝2.5)，6.68(1H，d，J＝8.5)。
Reference example 36
N-(4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-3-aminomethyl phenyl) sulphonamide ethyl acetate
4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-3-monomethylaniline (1.63g) and pyridine (0.81ml) are dissolved in the methylene dichloride (30ml), in ice-cooled lower dropping chlorine sulphonyl ethyl acetate (0.86ml), then at room temperature stirred 5 hours.In reaction mixture, add methyl alcohol (0.5ml), then decompression steams solvent, residue is made with extra care (elutriant: hexane/ethyl acetate=3/2), obtain light brown amorphous solid title compound 1.84g (yield 76%) with silica gel column chromatography.
1H?NMR(500MHz，CDCl 3)δppm：1.34(3H，t，J＝7.0)，1.47(9H，s)，1.78(2H，m)，1.89(2H，m)，2.22(3H，s)，3.43(2H，m)，3.62(2H，m)，3.90(2H，s)，4.29(2H，q，J＝7.0)，4.48(1H，m)，6.79(1H，d，J＝8.0)，7.12(2H，m)。
Reference example 37
N-(4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-3-aminomethyl phenyl)-N-(3-(3-cyano-phenyl)-2-(E)-propenyl) sulphonamide ethyl acetate
3-(3-cyano-phenyl)-2-(E)-propylene-1-alcohol (0.64g), N-(4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-3-aminomethyl phenyl) sulphonamide ethyl acetate (1.84g) and triphenylphosphine (1.26g) are dissolved in the methylene dichloride (40ml), at ice-cooled lower dropping diethyl azodiformate (0.76ml), under same temperature, stirred 1 hour.With the reaction mixture concentrating under reduced pressure, residue is made with extra care (elutriant: dichloromethane/ethyl acetate=12/1), obtain colourless amorphous solid title compound 1.90g (yield 79%) with silica gel column chromatography.
1H?NMR(500MHz，CDCl 3)δppm：1.36(3H，t，J＝7.0)，1.47(9H，s)，1.78(2H，m)，1.89(2H，m)，2.21(3H，s)，3.44(2H，m)，3.60(2H，m)，3.99(2H，s)，4.3?1(2H，q，J＝7.0)，4.46(2H，d，J＝6.5)，4.50(1H，m)，6.24(1H，dt，J＝16.0，6.5)，6.41(1H，d，J＝16.0)，6.80(1H，d，J＝8.0)，7.24(2H，m)，740(1H，t，J＝8.0)，7.50(1H，d，J＝7.5)，7.52(1H，d，J＝8.0)，7.56(1H，s)。
Reference example 38
3-bromo-5-cyano group toluene
3,5-dibromomethylbenzene (10.00g) is dissolved in the 1-Methyl-2-Pyrrolidone (70ml), adds cupric cyanide (I) (5.20g), then stirs 1.5 hours at 200 ℃.Add water after reaction mixture is cooled to room temperature, use ethyl acetate extraction, extraction liquid is used 1M hydrochloric acid, water and saturated common salt water washing, organic layer anhydrous magnesium sulfate drying successively.Decompression steams solvent, and residue is suspended in the mixed solvent (9/1) of hexane and ethyl acetate, then filters.Filtrate decompression is concentrated, and residue is made with extra care (elutriant: hexane/ethyl acetate=9/1.), obtain title compound 1.70g (yield 21%) with silica gel column chromatography.
1H?NMR(270MHz，CDCl 3)δppm：2.39(3H，s)，7.40(1H，s)，7.57(1H，s)，7.60(1H，s)。
Reference example 39
3-(3-cyano group-5-aminomethyl phenyl)-2-(E)-propylene-1-alcohol
In 1-t-butyldimethylsilyloxy base-2-propine (1.70g), add catecholborane (1.07ml), stirred 3 hours at 60 ℃.Reaction mixture is cooled to after the room temperature with toluene (20ml) dilution, then 20% ethanolic soln (3.40ml) that adds 3-bromo-5-cyano group toluene (1.40g), tetrakis triphenylphosphine palladium title complex (0.42g) and sodium ethylate stirred 3 hours at 100 ℃.Add entry in reaction mixture, then use extracted with diethyl ether, extraction liquid is used 1M aqueous sodium hydroxide solution, water and saturated common salt water washing, organic layer anhydrous sodium sulfate drying successively.Decompression steams solvent, and residue is made with extra care (elutriant: hexane/ethyl acetate=19/1), obtain silyl ether derivant 1.5g with silica gel column chromatography.
Then, the silyl ether derivant that obtains is dissolved in the tetrahydrofuran (THF) (30ml), then the tetrahydrofuran solution (7ml) at ice-cooled lower adding 1M tetrabutylammonium fluoride at room temperature stirred 1 hour.In reaction mixture, add entry, then use ethyl acetate extraction, extraction liquid water and saturated common salt water washing, organic layer anhydrous magnesium sulfate drying.Decompression steams solvent, and residue is made with extra care (elutriant: hexane/ethyl acetate=3/2), obtain yellow oily title compound 0.54g (2 step yield 43%) with silica gel column chromatography.
1H?NMR(270MHz，CDCl 3)δppm：2.38(3H，s)，4.35(2H，d，J＝5.0)，6.40(1H，dt，J＝16.0，5.0)，6.58(1H，d，J＝16.0)，7.33(1H，s)，7.40(1H，s)，7.46(1H，s)。
Reference example 40
N-(4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen) phenyl)-N-(3-(3-cyano group-5-aminomethyl phenyl)-2-(E)-propenyl) sulphonamide ethyl acetate
3-(3-cyano group-5-aminomethyl phenyl)-2-(E)-propylene-1-alcohol (0.54g), N-(4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen) phenyl) sulphonamide ethyl acetate (1.50g) and triphenylphosphine (1.10g) are dissolved in the methylene dichloride (30ml), at ice-cooled lower dropping diethyl azodiformate (0.66ml), then at room temperature stirred 4.5 hours.With the reaction mixture concentrating under reduced pressure, residue is made with extra care (elutriant: dichloromethane/ethyl acetate=19/1), obtain amorphous solid title compound 1.70g (yield 91%) with silica gel column chromatography.
1H?NMR(270MHz，CDCl 3)δppm：1.35(3H，t，J＝7.0)，1.47(9H，s)，1.65-1.80(2H，m)，1.85-2.00(2H，m)，2.36(3H，s)，3.25-3.40(2H，m)，3.60-3.75(2H，m)，3.98(2H，s)，4.30(2H，q，J＝7.0)，4.40-4.50(3H，m)，6.21(1H，dt，J＝16.0，6.0)，6.36(1H，d，J＝16.0)，6.90(2H，m)，7.30-7.45(5H，m)。
Reference example 41
3-(3-cyano group-4-fluorophenyl)-2-(E)-propylene-1-alcohol
In 1-t-butyldimethylsilyloxy base-2-propine (1.70g), add catecholborane (1.07ml), stirred 4 hours at 60 ℃.Reaction mixture is cooled to after the room temperature with toluene (20ml) dilution, then 20% ethanolic soln (3.40ml) that adds 5-bromo-2-fluorobenzonitrile (1.43g), tetrakis triphenylphosphine palladium title complex (0.42g) and sodium ethylate stirred 4 hours at 100 ℃.Add entry in reaction mixture, then use extracted with diethyl ether, extraction liquid is used 1M aqueous sodium hydroxide solution, water and saturated common salt water washing, organic layer anhydrous sodium sulfate drying successively.Decompression steams solvent, and residue is made with extra care (elutriant: hexane/ethyl acetate=19/1), obtain silyl ether derivant 1.33g with silica gel column chromatography.
Then, the silyl ether derivant that obtains is dissolved in the tetrahydrofuran (THF) (20ml), then the tetrahydrofuran solution (6ml) at ice-cooled lower adding 1M tetrabutylammonium fluoride stirred 1 hour under same temperature.In reaction mixture, add entry, then use ethyl acetate extraction, extraction liquid water and saturated common salt water washing, organic layer anhydrous magnesium sulfate drying.Decompression steams solvent, and residue is made with extra care (elutriant: hexane/ethyl acetate=3/2-1/1), obtain yellow oil title compound 0.48g (2 step yield 37%) with silica gel column chromatography.
1H?NMR(270MHz，CDC1 3)δppm：4.30-4.40(2H，m)，6.35(1H，dt，J＝16.0，5.0)，6.59(1H，d，J＝16.0)，7.18(1H，m)，7.55-7.65(2H，m)。
Reference example 42
N-(4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen) phenyl)-N-(3-(3-cyano group-4-fluorophenyl)-2-(E)-propenyl) sulphonamide ethyl acetate
3-(3-cyano group-4-fluorophenyl)-2-(E)-propylene-1-alcohol (0.48g), N-(4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen) phenyl) sulphonamide ethyl acetate (1.30g) and triphenylphosphine (1.10g) are dissolved in the methylene dichloride (30ml), at ice-cooled lower dropping diethyl azodiformate (0.60ml), then at room temperature stirred 1 hour.With the reaction mixture concentrating under reduced pressure, residue is made with extra care (elutriant: dichloromethane/ethyl acetate=19/1), obtain amorphous solid title compound 1.53g (yield 93%) with silica gel column chromatography.
1H?NMR(500MHz，CDCl 3)δppm：1.35(3H，t，J＝7.0)，1.47(9H，s)，1.70-1.80(2H，m)，1.85-1.95(2H，m)，3.30-3.40(2H，m)，3.65-3.75(2H，m)，3.97(2H，s)，4.30(2H，q，J＝7.0)，4.40-4.50(3H，m)，6.16(1H，dt，J＝16.0，6.0)，6.37(1H，d，J＝16.0)，6.91(2H，d，J＝9.0)，7.14(1H，m)，7.38(2H，d，J＝9.0)，7.45-7.55(2H，m)。
Reference example 43
3-(3-(N-(4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen) phenyl) amino)-1-(E)-propenyl) benzonitrile
3-cyano group phenylacrolein (6.0g), 4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen) aniline (11.3g) and 5A molecular sieve (15.0g) are suspended in the toluene (30ml) reflux 2 hours.Reaction mixture is by diatomite filtration, and filtrate decompression is concentrated, and residue obtains imido derivative (12.9g) with the mixture recrystallization of methylene dichloride and ethyl ester.
Then, resulting imido derivative is suspended in the ethanol (200ml), adds the Cerium II Chloride of catalytic amount, then at ice-cooled lower adding sodium borohydride (1.1g), under same temperature, stir.With the reaction mixture concentrating under reduced pressure, in residue, add water, use ethyl acetate extraction, extraction liquid saturated common salt water washing, organic layer anhydrous magnesium sulfate drying.Decompression steams solvent, and residue is made with extra care (elutriant: hexane/ethyl acetate=3/2), obtain yellow solid and wash with diisopropyl ether, obtain faint yellow crystallization title compound 10.0g (yield 60%) with silica gel column chromatography.
1H?NMR(270MHz，CDCl 3)δppm：1.46(9H，s)，1.60-1.80(2H，m)，1.80-1.95(2H，m)，3.20-3.35(2H，m)，3.65-3.80(2H，m)，3.93(2H，dd，J＝5.5，1.0)，4.28(1H，m)，6.39(1H，dt，J＝16.0，5.5)，6.61(1H，d，J＝16.0)，6.61(2H，d，J＝9.0)，6.81(2H，d，J＝9.0)，7.41(1H，t，J＝7.5)，7.51(1H，d，J＝7.5)，7.57(1H，d，J＝7.5)，7.63(1H，s)。
Reference example 44
3-(3-(N-(4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen) phenyl)-N-methyl " amino)-1-(E)-propenyl) benzonitrile
3-(3-(N-(4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen) phenyl) amino)-1-(E)-propenyl) benzonitrile (1000mg) and paraformaldehyde (138mg) are suspended in the methylene dichloride (20ml), at ice-cooled lower adding acetic acid (0.26ml) and sodium cyanoborohydride (144mg), then at room temperature stir and spend the night.In reaction mixture, add methyl alcohol (20ml), stirred 5 hours at 30 ℃, add water, use ethyl acetate extraction, extraction liquid saturated common salt water washing, organic layer anhydrous magnesium sulfate drying.Decompression steams solvent after filtering, and residue is made with extra care (elutriant: hexane/ethyl acetate=3/2), obtain yellow oily title compound 761mg (yield 74%) with silica gel column chromatography.
1H?NMR(270MHz，CDCl 3)δppm：1.47(9H，s)，1.72(2H，m)，1.87(2H，m)，2.92(3H，s)，3.28(2H，m)，3.71(2H，m)，4.02(2H，d，J＝5.0)，4.29(1H，m)，6.32(1H，dt，J＝16.0，5.0)，6.51(1H，d，J＝16.0)，6.72(2H，d，J＝9.0)，6.86(2H，d，J＝9.0)，7.39(1H，t，J＝7.5)，7.49(1H，d，J＝7.5)，7.56(1H，d，J＝7.5)，7.62(1H，s)。
Reference example 45
3-(3-(N-(4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen) phenyl)-N-ethylamino)-1-(E)-propenyl) benzonitrile
3-(3-(N-(4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen) phenyl) amino)-1-(E)-propenyl) benzonitrile (1000mg) and acetaldehyde (0.52ml) are dissolved in the mixed solvent of methylene dichloride (10ml) and methyl alcohol (20ml), at ice-cooled lower adding acetic acid (0.26ml) and sodium cyanoborohydride (144mg), under same temperature, stirred 2 hours, then at room temperature stir and spend the night.In reaction mixture, add entry, use ethyl acetate extraction, extraction liquid saturated common salt water washing, organic layer anhydrous magnesium sulfate drying.Decompression steams solvent after filtering, and residue is made with extra care (elutriant: hexane/ethyl acetate=4/1-2/1), obtain yellow oily title compound 661mg (yield 62%) with silica gel column chromatography.
1H?NMR(270MHz，CDCl 3)δppm：1.16(3H，t，J＝7.0)，1.46(9H，s)，1.72(2H，m)，1.87(2H，m)，3.25(2H，m)，3.36(2H，q，J＝7.0)，3.71(2H，m)，4.01(2H，d，J＝5.0)，4.26(1H，m)，6.31(1H，dt，J＝16.0，5.0)，6.50(1H，d，J＝16.0)，6.69(2H，d，J＝9.0)，6.84(2H，d，J＝9.0)，7.39(1H，t，J＝7.5)，7.49(1H，d，J＝7.5)，7.55(1H，d，J＝7.5)，7.61(1H，s)。
Reference example 46
3-(3-(N-(4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen) phenyl)-N-isopropylamino)-1-(E)-propenyl) benzonitrile
3-(3-(N-(4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen) phenyl) amino)-1-(E)-propenyl) benzonitrile (1500mg) is dissolved in the acetone (20ml), at ice-cooled lower adding acetic acid (0.20ml) and sodium cyanoborohydride (214mg), at room temperature stir and spend the night, then reflux added entry in 8 hours in reaction mixture, use ethyl acetate extraction, extraction liquid saturated common salt water washing, the organic layer anhydrous magnesium sulfate drying.Decompression steams solvent after filtering, and residue is made with extra care (elutriant: hexane/ethyl acetate=4: 1), obtain faint yellow oily title compound 583mg (yield 35%) with silica gel column chromatography.
1H?NMR(270MHz，CDCl 3)δppm：1.18(6H，d，J＝6.5)，1.46(9H，s)，1.60-1.80(2H，m)，1.80-1.95(2H，m)，3.26(2H，m)，3.71(2H，m)，3.91(2H，d，J＝4.5)，4.00(1H，m)，4.26(1H，m)，6.33(1H，dt，J＝16.0，4.5)，6.53(1H，d，J＝16.0)，6.73(2H，d，J＝9.0)，6.82(2H，d，J＝9.0)，7.38(1H，t，J＝7.5)，7.47(1H，d，J＝7.5)，7.53(1H，d，J＝7.5)，7.60(1H，s)。
Reference example 47
3-(3-(N-benzyl-N-(4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen) phenyl) amino)-1-(E)-propenyl) benzonitrile
3-(3-(N-(4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen) phenyl) amino)-1-(E)-propenyl) benzonitrile (1000mg) and phenyl aldehyde (0.52ml) are dissolved in the mixed solvent of methylene dichloride (10ml) and methyl alcohol (20ml), at ice-cooled lower adding acetic acid (0.26ml) and sodium cyanoborohydride (144mg), then reflux is 10 hours.In reaction mixture, add entry, use ethyl acetate extraction, extraction liquid saturated common salt water washing, organic layer anhydrous magnesium sulfate drying.Decompression steams solvent after filtering, and residue is made with extra care (elutriant: hexane/ethyl acetate=4/1-2/1), obtain yellow oily title compound 924mg (yield 76%) with silica gel column chromatography.
1H?NMR(270MHz，CDC1 3)δppm：1.46(9H，s)，1.70(2H，m)，1.87(2H，m)，3.26(2H，m)，3.69(2H，m)，4.11(2H，d，J＝5.0)，4.26(1H，m)，4.52(2H，s)，6.32(1H，dt，J＝16.0，5.0)，6.48(1H，d，J＝16.0)，6.71(2H，d，J＝9.0)，6.81(2H，d，J＝9.0)，7.20-7.60(9H，m)。
Reference example 48
N-(4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen) phenyl)-N-(3-(3-cyano-phenyl)-2-(E)-propenyl) ethanamide
3-(3-(N-(4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen) phenyl) amino)-1-(E)-propenyl) benzonitrile (503mg) and pyridine (0.14ml) are dissolved in the methylene dichloride (10ml), at ice-cooled lower adding acetic anhydride (0.13ml), then at room temperature stirred 1 hour.In reaction mixture, add entry, use ethyl acetate extraction, extraction liquid saturated common salt water washing, organic layer anhydrous magnesium sulfate drying.Decompression steams solvent after filtering, residue is made with extra care (elutriant: hexane/ethyl acetate=1/1-ethyl acetate) with silica gel column chromatography, the yellow crystal that obtains is cleaned with diisopropyl ether, obtains faint yellow crystallization title compound 403mg (yield 50%).
1H?NMR(270MHz，CDCl 3)δppm：1.47(9H，s)，1.88(3H，s)，1.70-1.95(4H，m)，3.33(2H，m)，3.70(2H，m)，4.41(2H，d，J＝5.5)，4.47(1H，m)，6.32(1H，dt，J＝16.0，5.5)，6.38(1H，d，J＝16.0)，6.91(2H，d，J＝9.0)，7.07(2H，d，J＝9.0)，7.40(1H，t，J＝8.0)，7.51(1H，d，J＝8.0)，7.55(1H，d，J＝8.0)，7.58(1H，s)。
Reference example 49
N-(4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen) phenyl)-N-(3-(3-cyano-phenyl)-2-(E)-propenyl)-2-hydroxyl acetamide
3-(3-(N-(4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen) phenyl) amino)-1-(E)-propenyl) benzonitrile (1000mg) and pyridine (0.28ml) are dissolved in the methylene dichloride (20ml), at ice-cooled lower adding alpha-Acetoxyacetyl chloride (0.27ml), under same temperature, stirred 1 hour.In reaction mixture, add entry, use ethyl acetate extraction, extraction liquid saturated common salt water washing, organic layer anhydrous magnesium sulfate drying.Decompression steams solvent after filtering, and residue is made with extra care (elutriant: hexane/ethyl acetate=2/3), obtain colourless amorphous solid intermediate compound 1232mg with silica gel column chromatography.
Then, resulting intermediate compound is dissolved in the methyl alcohol (20ml), adds salt of wormwood (640mg), at room temperature stirred 1 hour.In reaction mixture, add entry, use ethyl acetate extraction, extraction liquid saturated common salt water washing, organic layer anhydrous magnesium sulfate drying.Decompression steams solvent after filtering, and residue is made with extra care (elutriant: hexane/ethyl acetate=1/2), obtain colourless amorphous solid title compound 977mg (yield 86%) with silica gel column chromatography.
1H?NMR(270MHz，CDCl 3)δppm：1.47(9H，s)，1.76(2H，m)，1.93(2H，m)，3.28-3.40(2H，m)，3.60-3.80(2H，m)，3.81(2H，d，J＝4.5)，4.46(2H，d，J＝6.5)，4.47(1H，m)，6.30(1H，dt，J＝16.0，6.5)，6.44(1H，d，J＝16.0)，6.93(2H，d，J＝9.0)，7.07(2H，d，J＝9.0)，7.42(1H，t，J＝7.5)，7.53(1H，d，J＝7.5)，7.56(1H，d，J＝7.5)，7.59(1H，s)。
Reference example 50
2-(N-(4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen) phenyl)-N-(3-(3-cyano-phenyl)-2-(E)-propenyl) amino) ethyl acetate
3-(3-(N-(4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen) phenyl) amino)-1-(E)-propenyl) benzonitrile (1.00g) is dissolved in N, in the dinethylformamide (20ml), add salt of wormwood (0.96g) and ethyl bromoacetate (0.62ml), stirred 9 hours at 70 ℃.In reaction mixture, add entry, use ethyl acetate extraction, extraction liquid saturated common salt water washing, organic layer anhydrous magnesium sulfate drying.Decompression steams solvent after filtering, and residue is made with extra care (elutriant: hexane/ethyl acetate=2/1), obtain yellow oily title compound 1.31g (quantitative yield) with silica gel column chromatography.
1H?NMR(270MHz，CDCl 3)δppm：1.26(3H，t，J＝7.0)，1.46(9H，s)，1.71(2H，m)，1.88(2H，m)，3.27(2H，m)，3.71(2H，m)，4.03(2H，m)，4.15-4.35(5H，m)，6.36(1H，dt，J＝16.0，5.0)，6.57(1H，d，J＝16.0)，6.65(2H，d，J＝9.0)，6.83(2H，d，J＝9.0)，7.40(1H，t，J＝7.5)，7.50(1H，d，J＝7.5)，7.57(1H，d，J＝7.5)，7.63(1H，s)。
Reference example 51
2-(N-(4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen) phenyl)-N-(3-(3-cyano-phenyl)-2-(E)-propenyl) amino) ethyl propionate
3-(3-(N-(4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen) phenyl) amino)-1-(E)-propenyl) benzonitrile (1200mg) is dissolved in N, in the dinethylformamide (20ml), add salt of wormwood (1710mg) and 2 bromopropionic acid ethyl ester (1.5ml), stirred 12 hours at 100 ℃.In reaction mixture, add entry, use ethyl acetate extraction, extraction liquid saturated common salt water washing, organic layer anhydrous magnesium sulfate drying.Decompression steams solvent after filtering, and residue is made with extra care (elutriant: hexane/ethyl acetate=2/1), obtain yellow oily title compound 882mg (yield 60%) with silica gel column chromatography.
1H?NMR(270MHz，CDCl 3)δppm：1.24(3H，t，J＝7.0)，1.46(9H，s)，1.50(3H，d，J＝7.0)，1.71(2H，m)，1.87(2H，m)，3.27(2H，m)，3.70(2H，m)，4.17(2H，q，J＝7.0)，4.01-4.32(3H，m)，4.38(1H，q，J＝7.0)，6.36(1H，dt，J＝16.0，4.5)，6.57(1H，d，J＝16.0)，6.73(2H，d，J＝9.0)，6.82(2H，d，J＝9.0)，7.39(1H，t，J＝8.0)，7.49(1H，d，J＝8.0)，7.55(1H，d，J＝8.0)，7.61(1H，s)。
Reference example 52
N-(4-methoxymethoxy phenyl) sulphonamide ethyl acetate
4-methoxymethoxy aniline (20.9g) and pyridine (33ml) are dissolved in the methylene dichloride (400ml), in ice-cooled lower dropping chlorine sulphonyl ethyl acetate (18.0ml), at room temperature stir and spend the night.In reaction mixture, add entry, use ethyl acetate extraction, extraction liquid saturated common salt water washing, organic layer anhydrous magnesium sulfate drying.Decompression steams solvent after filtering, and residue is made with extra care (elutriant: hexane/ethyl acetate=3/2), obtain brown oily title compound 28.0g (yield 67%) with silica gel column chromatography.
1H?NMR(270MHz，CDCl 3)δppm：1.33(3H，t，J＝7.0)，3.48(3H，s)，3.90(2H，s)，4.29(2H，q，J＝7.0)，5.16(2H，s)，7.03(2H，d，J＝9.0)，7.28(2H，d，J＝9.0)。
Reference example 53
N-(3-(3-cyano-phenyl)-2-(E)-propenyl)-N-(4-methoxymethoxy phenyl) sulphonamide ethyl acetate
3-(3-cyano-phenyl)-2-(E)-propylene-1-alcohol (0.525g), N-(4-methoxymethoxy phenyl) sulphonamide ethyl acetate (1.00g) and triphenylphosphine (1.12g) are dissolved in the methylene dichloride (30ml), drip diethyl azodiformate (0.66ml), then at room temperature stirred 3.5 hours.With the reaction mixture concentrating under reduced pressure, residue is made with extra care (elutriant: hexane/ethyl acetate=3/2), obtain yellow oily title compound 1.38g (yield 94%) with silica gel column chromatography.
1H?NMR(270MHz，CDCl 3)δppm：1.37(3H，t，J＝7.0)，3.48(3H，s)，3.99(2H，s)，4.32(2H，q，J＝7.0)，4.49(2H，d，J＝6.0)，5.18(2H，s)，6.25(1H，dt，J＝16.0，6.0)，6.42(1H，d，J＝16.0)，7.06(2H，d，J＝9.0)，7.40(1H，t，J＝7.0)，7.41(2H，d，J＝9.0)，7.52(1H，d，J＝7.0)，7.54(1H，d，J＝7.0)，7.56(1H，s)。
Reference example 54
N-(3-(3-cyano-phenyl)-2-(E)-propenyl)-N-(4-hydroxy phenyl) sulphonamide ethyl acetate
N-(3-(3-cyano-phenyl)-2-(E)-propenyl)-N-(4-methoxymethoxy phenyl) sulphonamide ethyl acetate (10.7g) is dissolved in the ethyl acetate (120ml), at ice-cooled lower adding 4M hydrogenchloride ethyl acetate solution (80ml), then at room temperature stirred 4 hours.With the reaction mixture concentrating under reduced pressure, in residue, add water, use ethyl acetate extraction, extraction liquid saturated common salt water washing, organic layer anhydrous magnesium sulfate drying.Decompression steams solvent, and residue is made with extra care (elutriant: hexane/ethyl acetate=1/1), obtain yellow oily title compound 9.1g (yield 95%) with silica gel column chromatography.
1H?NMR(270MHz，CDCl 3)δppm：1.35(3H，t，J＝7.0)，3.98(2H，s)，4.30(2H，q，J＝7.0)，4.46(2H，d，J＝6.0)，6.23(1H，dt，J＝16.0，6.0)，6.39(1H，d，J＝16.0)，6.84(2H，d，J＝9.0)，7.34(2H，d，J＝9.0)，7.39(1H，t，J＝7.5)，7.50(2H，m)，7.54(1H，s)。
Reference example 55
N-(4-(1-tertbutyloxycarbonyl pyrrolidin-3-yl oxygen) phenyl)-N-(3-(3-cyano-phenyl)-2-(E)-propenyl) sulphonamide ethyl acetate
N-(3-(3-cyano-phenyl)-2-(E)-propenyl)-N-(4-hydroxy phenyl) sulphonamide ethyl acetate (800mg), 1-tertbutyloxycarbonyl-3-hydroxyl pyrrolidine (450mg) and triphenylphosphine (680mg) are dissolved in the tetrahydrofuran (THF) (20ml), add diethyl azodiformate (0.68ml), then at room temperature stir and spend the night.With the reaction mixture concentrating under reduced pressure, residue is made with extra care (elutriant: dichloromethane/ethyl acetate=10/1), obtain colourless amorphous solid title compound 900mg (yield 79%) with silica gel column chromatography.
1H?NMR(270MHz，CDCl 3)δppm：1.36(3H，t，J＝7.0)，1.46(9H，s)，2.00-2.25(2H，m)，3.40-3.70(4H，m)，3.98(2H，s)，4.31(2H，q，J＝7.0)，4.48(2H，d，J＝6.5)，4.85(1H，m)，6.24(1H，dt，J＝16.0，6.5)，6.41(1H，d，J＝16.0)，6.87(2H，d，J＝9.0)，7.35-7.45(3H，m)，7.45-7.60(3H，m)。
Reference example 56
3-(3-(N-(4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen) phenyl)-N-(2-hydroxyethyl) amino)-1-(E)-propenyl) benzonitrile
3-(3-(N-(4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen) phenyl) amino)-1-(E)-propenyl) benzonitrile (1000mg) and glycollic aldehyde dimer (277mg) are dissolved in the methylene dichloride (20ml), at ice-cooled lower adding acetic acid (0.13ml) and sodium cyanoborohydride (72mg), under same temperature, stirred 5 hours, then at room temperature stirred 4 hours.In reaction mixture, add entry, use ethyl acetate extraction, extraction liquid saturated common salt water washing, organic layer anhydrous magnesium sulfate drying.Decompression steams solvent after filtering, and residue is made with extra care (elutriant: hexane/ethyl acetate=4/3), obtain yellow oily title compound 1100mg (yield 50%) with silica gel column chromatography.
1H?NMR(500MHz，CDCl 3)δppm：1.46(9H，s)，1.72(2H，m)，1.89(2H，m)，3.28(2H，m)，3.45(2H，t，J＝5.5)，3.71(2H，m)，3.79(2H，m)，4.07(2H，m)，4.30(1H，m)，6.31(1H，dt，J＝16.0，5.5)，6.48(1H，d，J＝16.0)，6.80(2H，d，J＝9.0)，6.84(2H，d，J＝9.0)，7.39(1H，t，J＝8.0)，7.49(1H，d，J＝8.0)，7.54(1H，d，J＝8.0)，7.60(1H，s)。
Reference example 57
5-nitro salicylic acid ethyl ester
5-nitro salicylic acid (10.8g) is dissolved in the ethanol (100ml), at room temperature adds the vitriol oil (92.0g), and then reflux is 7.5 hours.Reaction mixture neutralizes with aqueous sodium hydroxide solution, then use ethyl acetate extraction, extraction liquid is used saturated sodium bicarbonate aqueous solution, 0.5M hydrochloric acid and saturated common salt water washing successively, the organic layer anhydrous magnesium sulfate drying, decompression steams solvent after filtering, and obtains yellow solid title compound 10.7g (yield 85%).
1H?NMR(400MHz，CDCl 3)δppm：1.47(3H，t，J＝7.0)，4.49(2H，q，J＝7.0)，7.09(1H，d，J＝9.0)，8.33(1H，dd，J＝9.0，3.0)，8.79(1H，d，J＝3.0)。
Reference example 58
4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-3-ethoxycarbonyl oil of mirbane
1-tertbutyloxycarbonyl-4-hydroxy piperidine (10.2g), 5-nitro salicylic acid ethyl ester (10.7g) and triphenylphosphine (17.3g) are dissolved in the methylene dichloride (200ml), at ice-cooled lower dropping diethyl azodiformate (10.4ml), then at room temperature stirred 4 hours.With the reaction mixture concentrating under reduced pressure, residue is made with extra care (elutriant: hexane/ethyl acetate=3/1), add hexane in the yellow solid that obtains, obtain white solid title compound 12.3g (yield 61%) after the filtration with silica gel column chromatography.
1H?NMR(400MHz，CDCl 3)δppm：1.40(3H，t，J＝7.0)，1.47(9H，s)，1.91(4H，m)，3.58(4H，m)，4.39(2H，q，J＝7.0)，4.79(1H，m)，7.04(1H，d，J＝9.0)，8.32(1H，dd，J＝9.0，3.0)，8.69(1H，d，J＝3.0)。
Reference example 59
4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-3-ethoxycarbonyl aniline
4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-3-ethoxycarbonyl oil of mirbane (5.0g) is dissolved in the methyl alcohol (75ml), adds palladium carbon catalyzer (0.5g), then at room temperature stirs in atmosphere of hydrogen 2.5 hours.Reaction mixture is filtered, and filtrate decompression is concentrated, obtains grey oily title compound 4.6g (yield 99%).
1H?NMR(400MHz，CDCl 3)δppm：1.37(3H，t，J＝7.0)，1.46(9H，s)，1.70-1.95(4H，m)，3.25-3.40(2H，m)，3.60-3.75(2H，m)，4.30-4.40(1H，m)，4.34(2H，q，J＝7.0)，6.77(1H，dd，J＝9.0，3.0)，6.83(1H，d，J＝9.0)，7.12(1H，d，J＝3.0)。
Reference example 60
N-(4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-3-carbethoxy phenyl) sulphonamide ethyl acetate
4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-3-ethoxycarbonyl aniline (4.6g) and pyridine (2.0ml) are dissolved in the methylene dichloride (70ml), in ice-cooled lower dropping chlorine sulphonyl ethyl acetate (2.5ml), at room temperature stirred 6 hours.With the reaction mixture concentrating under reduced pressure, filter insolubles (hexane/ethyl acetate=1: 1), filtrate is made with extra care (elutriant: hexane/ethyl acetate=1/1), obtain orange amorphous solid title compound 5.9g (yield 90%) with silica gel column chromatography.
1H?NMR(400MHz，CDCl 3)δ?ppm：1.34(3H，t，J＝7.0)，1.37(3H，t，J＝7.0)，1.47(9H，s)，1.75-1.95(4H，m)，3.45-3.55(2H，m)，3.55-3.65(2H，m)，3.91(2H，s)，4.30(2H，q，J＝7.0)，4.35(2H，q，J＝7.0)，4.59(1H，m)，6.97(1H，d，J＝9.0)，7.47(1H，dd，J＝9.0，3.0)，7.70(1H，d，J＝3.0)。
Reference example 61
N-(4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-3-carbethoxy phenyl)-N-(3-(3-cyano-phenyl)-2-(E)-propenyl) sulphonamide ethyl acetate
3-(3-cyano-phenyl)-2-(E)-propylene-1-alcohol (1.7g), N-(4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-3-carbethoxy phenyl) sulphonamide ethyl acetate (5.9g) and triphenylphosphine (4.5g) are dissolved in the methylene dichloride (100ml), drip diethyl azodiformate (2.7ml), then at room temperature stirred 3 hours.With the reaction mixture concentrating under reduced pressure, residue is made with extra care (elutriant: hexane/ethyl acetate=2/1), obtain yellow amorphous solid title compound 5.7g (yield 81%) with silica gel column chromatography.
1H?NMR(500MHz，CDCl 3)δppm：1.35(3H，t，J＝7.0)，1.36(3H，t，J＝7.0)，1.46(9H，s)，1.75-1.95(4H，m)，3.45-3.65(4H，m)，3.99(2H，s)，4.31(2H，q，J＝7.0)，4.35(2H，q，J＝7.0)，4.49(2H，d，J＝7.0)，4.62(1H，m)，6.23(1H，dt，J＝16.0，7.0)，6.41(1H，d，J＝16.0)，6.97(1H，m)，7.40(1H，m)，7.45-7.60(4H，m)，7.89(1H，m)。
Reference example 62
3-bromo-4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen) oil of mirbane
1-tertbutyloxycarbonyl-4-hydroxy piperidine (2.7g), 3-bromo-4-hydroxyl oil of mirbane (1.9g) are (according to J.Org.Chem. 63, 4199 (1998) described methods are synthetic from the 3-bromo nitrobenzene) and triphenylphosphine (4.4g) be dissolved in the methylene dichloride (50ml), dropping diethyl azodiformate (2.7ml) then at room temperature stirred 11.5 hours.With the reaction mixture concentrating under reduced pressure, residue is made with extra care (elutriant: hexane/ethyl acetate=2/1), obtain yellow oily title compound 3.1g (yield 91%) with silica gel column chromatography.
1H?NMR(400MHz，CDCl 3)δ?ppm：1.48(9H，s)，1.91(4H，m)，3.59(4H，m)，4.75(1H，m)，6.96(1H，d，J＝9.0)，8.19(1H，dd，J＝9.0，3.0)，8.48(1H，d，J＝3.0)。
Reference example 63
3-bromo-4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen) aniline
3-bromo-4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen) oil of mirbane (3.1g) is dissolved in the acetic acid (40ml), adds zinc powder (10.0g is divided into 10 parts), then at room temperature stirs 5 hours.Reaction mixture filters by Celite (registered trademark), filtrate is used ethyl acetate extraction, extraction liquid is used saturated sodium bicarbonate aqueous solution, water and saturated common salt water washing successively, the organic layer anhydrous magnesium sulfate drying, decompression steams solvent after filtering, residue is made with extra care (elutriant: hexane/ethyl acetate=1/1), obtain dark brown amorphous solid title compound 2.0g (yield 69%) with silica gel column chromatography.
1H?NMR(400MHz，CDCl 3)δppm：1.47(9H，s)，1.70-1.90(4H，m)，3.30-3.40(2H，m)，3.65-3.75(2H，m)，4.30(1H，m)，6.57(1H，dd，J＝9.0，3.0)，6.78(1H，d，J＝9.0)，6.91(1H，d，J＝3.0)。
Reference example 64
N-(3-bromo-4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen) phenyl) sulphonamide ethyl acetate
3-bromo-4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen) aniline (2.0g) and pyridine (0.9ml) are dissolved in the methylene dichloride (60ml), in ice-cooled lower dropping chlorine sulphonyl ethyl acetate, at room temperature stir 2 hours.With the reaction mixture concentrating under reduced pressure, residue is made with extra care (elutriant: hexane/ethyl acetate=1/1), obtain yellow amorphous solid title compound 2.1g (yield 74%) with silica gel column chromatography.
1H?NMR(500MHz，CDCl 3)δppm：1.34(3H，t，J＝7.0)，1.47(9H，s)，1.75-1.95(4H，m)，3.45-3.55(2H，m)，3.55-3.65(2H，m)，3.92(2H，s)，4.29(2H，q，J＝7.0)，4.55(1H，m)，6.85-6.95(2H，m)，7.56(1H，m)。
Reference example 65
N-(3-bromo-4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen) phenyl)-N-(3-(3-cyano-phenyl)-2-(E)-propenyl) sulphonamide ethyl acetate
3-(3-cyano-phenyl)-2-(E)-propylene-1-alcohol (0.7g), N-(3-bromo-4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen) phenyl) sulphonamide ethyl acetate (2.1g) and triphenylphosphine (1.4g) are dissolved in the methylene dichloride (30ml), drip diethyl azodiformate (0.9ml), then at room temperature stirred 6 hours.With the reaction mixture concentrating under reduced pressure, residue is made with extra care (elutriant: dichloromethane/ethyl acetate=19/1), obtain colourless amorphous solid title compound 2.2g (yield 82%) with silica gel column chromatography.
1H?NMR(400MHz，CDCl 3)δppm：1.36(3H，t，J＝7.0)，1.47(9H，s)，1.75-1.95(4H，m)，3.45-3.65(4H，m)，3.99(2H，s)，4.31(2H，q，J＝7.0)，4.46(2H，d，J＝6.0)，4.58(1H，m)，6.22(1H，dt，J＝16.0，6.0)，6.42(1H，d，J＝16.0)，6.90(1H，m)，7.37(1H，m)，7.42(1H，m)，7.45-7.60(3H，m)，7.71(1H，m)。
Reference example 66
2-sec.-propyl-4-nitrophenols
2-isopropyl-phenol (4.1ml) is dissolved in the acetic acid (30ml), at ice-cooled lower adding 69% nitric acid (4ml), stirs 30 minutes under same temperature.Reaction mixture is poured in the frozen water, and then with the methyl tertiary butyl ether extraction, extraction liquid is water and saturated common salt water washing successively, the organic layer anhydrous sodium sulfate drying.Decompression steams solvent after filtering, and residue is made with extra care (elutriant: hexane/ethyl acetate=4/1), obtain yellow solid title compound 2.66g (yield 49%) with silica gel column chromatography.
1H?NMR(400MHz，CDCl 3)δppm：1.30(6H，d，J＝7.0)，3.25(1H，m)，6.82(1H，d，J＝9.0)，8.01(1H，dd，J＝9.0，2.5)，8.13(1H，d，J＝2.5)。
Reference example 67
4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-3-sec.-propyl oil of mirbane
(2.96g, 2-sec.-propyl-4-nitrophenols (2.66g) and triphenylphosphine (5.00g) are dissolved in the methylene dichloride (80ml) 1-tertbutyloxycarbonyl-4-hydroxy piperidine, add diethyl azodiformate (3.0ml), then at room temperature stirred 2 hours.With the reaction mixture concentrating under reduced pressure, residue is made with extra care (elutriant: methylene dichloride), obtain dark brown solid title compound 4.07g (yield 76%) with silica gel column chromatography.
1H?NMR(400MHz，CDCl 3)δppm：1.26(6H，d，J＝7.0)，1.48(9H，s)，1.80-1.90(2H，m)，1.90-2.05(2H，m)，3.33(1H，m)，3.52(2H，m)，3.62(2H，m)，4.67(1H，m)，6.87(1H，d，J＝9.0)，8.08(1H，dd，J＝9.0，3.0)，8.12(1H，d，J＝3.0)。
Reference example 68
4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-3-isopropyl aniline
4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-3-sec.-propyl oil of mirbane (4.1g) is dissolved in the methyl alcohol (70ml), adds palladium carbon catalyzer (0.4g), then at room temperature stirs in atmosphere of hydrogen 3 hours.Reaction mixture is filtered, and filtrate decompression is concentrated, and residue is made with extra care (elutriant: hexane/ethyl acetate=3/2), obtain red oily title compound 2.8g (yield 74%) with silica gel column chromatography.
1H?NMR(400MHz，CDCl 3)δppm：1.18(6H，d，J＝7.0)，1.47(9H，s)，1.70-1.80(2H，m)，1.85-1.95(2H，m)，3.20-3.40(3H，m)，3.60-3.75(2H，m)，4.29(1H，m)，6.47(1H，dd，J＝9.0，3.0)，6.60(1H，d，J＝3.0)，6.68(1H，d，J＝9.0)。
Reference example 69
N-(4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-3-isopropyl phenyl) sulphonamide ethyl acetate
4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-3-isopropyl aniline (2.8g) and pyridine (1.4ml) are dissolved in the methylene dichloride (80ml), in ice-cooled lower dropping chlorine sulphonyl ethyl acetate (1.5ml), then at room temperature stirred 4 hours.With the reaction mixture concentrating under reduced pressure, residue is made with extra care (elutriant: dichloromethane/ethyl acetate=19/1), obtain yellow amorphous solid title compound 3.3g (yield 80%) with silica gel column chromatography.
1H?NMR(500MHz，CDCl 3)δppm：1.20(6H，d，J＝7.0)，1.37(3H，t，J＝7.0)，1.48(9H，s)，1.75-1.85(2H，m)，1.85-1.95(2H，m)，3.30(1H，m)，3.40-3.50(2H，m)，3.55-3.65(2H，m)，3.90(2H，s)，4.30(2H，q，J＝7.0)，4.50(1H，m)，6.80(1H，d，J＝9.0)，7.13(1H，dd，J＝9.0，3.0)，7.17(1H，d，J＝3.0)。
Reference example 70
N-(4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-3-isopropyl phenyl)-N-(3-(3-cyano-phenyl)-2-(E)-propenyl) sulphonamide ethyl acetate
3-(3-cyano-phenyl)-2-(E)-propylene-1-alcohol (0.5g), N-(4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-3-isopropyl phenyl) sulphonamide ethyl acetate (1.5g) and triphenylphosphine (1.1g) are dissolved in the methylene dichloride (50ml), at ice-cooled lower dropping diethyl azodiformate (0.7ml), then at room temperature stirred 4 hours.With the reaction mixture concentrating under reduced pressure, residue is made with extra care (elutriant: dichloromethane/ethyl acetate=19/1), obtain yellow amorphous solid title compound 1.8g (yield 96%) with silica gel column chromatography.
1H?NMR(500MHz，CDCl 3)δppm：1.18(6H，d，J＝7.0)，1.36(3H，t，J＝7.0)，1.47(9H，s)，1.75-1.85(2H，m)，1.85-1.95(2H，m)，3.29(1H，m)，3.40-3.50(2H，m)，3.55-3.65(2H，m)，3.99(2H，s)，4.31(2H，q，J＝7.0)，4.46(2H，d，J＝6.0)，4.52(1H，m)，6.25(1H，dt，J＝16.0，6.0)，6.40(1H，d，J＝16.0)，6.81(1H，d，J＝9.0)，7.22(1H，dd，J＝9.0，3.0)，7.31(1H，d，J＝3.0)，7.40(1H，m)，7.45-7.60(3H，m)。
With reference to you 71
4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-3-carboxyl oil of mirbane
4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-3-ethoxycarbonyl oil of mirbane (1.0g) is dissolved in the ethanol (10ml), adds potassium hydroxide (0.2g) aqueous solution (0.5ml), and then reflux is 2 hours.Reaction mixture neutralizes with 1 M hydrochloric acid, then uses ethyl acetate extraction, and extraction liquid is water and saturated common salt water washing successively, the organic layer anhydrous magnesium sulfate drying.Decompression steams solvent after filtering, and obtains yellow solid title compound 0.9g (yield 96%).
1H?NMR(500MHz，CDCl 3)δppm：1.48(9H，s)，1.85-1.95(2H，m)，2.00-2.10(2H，m)，3.45-3.55(2H，m)，3.65-3.75(2H，m)，4.87(1H，m)，7.13(1H，d，J＝9.0)，8.39(1H，dd，J＝9.0，3.0)，8.93(1H，d，J＝3.0)。
Reference example 72
4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-3-formamyl oil of mirbane
4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-3-carboxyl oil of mirbane (0.9g) is dissolved in the methylene dichloride (20ml), at ice-cooled lower adding isobutyl chlorocarbonate (0.3ml) and triethylamine (0.4ml), after stirring 1 hour under the same temperature, add 28% ammoniacal liquor (0.2ml), at room temperature stirred 1 hour.With the reaction mixture concentrating under reduced pressure, residue is made with extra care (elutriant: methylene chloride/methanol=19/1), obtain faint yellow amorphous solid title compound 0.9g (yield 98%) with silica gel column chromatography.
1H?NMR(500MHz，CDCl 3)δppm：1.48(9H，s)，1.80-1.90(2H，m)，2.05-2.20(2H，m)，3.30-3.40(2H，m)，3.75-3.90(2H，m)，4.81(1H，m)，7.11(1H，d，J＝9.0)，8.33(1H，dd，J＝9.0，3.0)，9.09(1H，d，J＝3.0)。
Reference example 73
4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-3-formamyl aniline
4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-3-formamyl oil of mirbane (5.7g) is dissolved in the methyl alcohol (80ml), adds palladium carbon catalyzer (0.6g), then at room temperature stirs in atmosphere of hydrogen 2.5 hours.Reaction mixture is filtered, and filtrate is made with extra care (elutriant: methylene chloride/methanol=19/1), obtain faint yellow amorphous solid title compound 4.8g (yield 91%) with silica gel column chromatography.
1H?NMR(500MHz，CDCl 3)δppm：1.47(9H，s)，1.65-1.80(2H，m)，1.95-2.05(2H，m)，3.19(2H，m)，3.75-3.85(2H，m)，4.44(1H，m)，6.78(1H，dd，J＝9.0，3.0)，6.84(1H，d，J＝9.0)，7.50(1H，d，J＝3.0)。
Reference example 74
N-(4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-3-formamyl phenyl) sulphonamide ethyl acetate
4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-3-formamyl aniline (4.8g) and pyridine (2.3ml) are dissolved in the methylene dichloride (80ml); in ice-cooled lower dropping chlorine sulphonyl ethyl acetate (2.5ml), then at room temperature stirred 6 hours.With the reaction mixture concentrating under reduced pressure, residue is made with extra care (elutriant: methylene chloride/methanol=19/1), add ether in the gained orange solids, obtain faint yellow solid title compound 3.7g (yield 53%) after the filtration with silica gel column chromatography.
1H?NMR(500MHz，CDCl 3)δppm：1.32(3H，t，J＝7.0)，1.47(9H，s)，1.70-1.85(2H，m)，2.00-2.1?5(2H，m)，3.27(2H，m)，3.75-3.85(2H，m)，3.94(2H，s)，4.28(2H，q，J＝7.0)，4.65(1H，m)，7.02(1H，d，J＝9.0)，7.59(1H，dd，J＝9.0，3.0)，8.12(1H，d，J＝3.0)。
Reference example 75
N-(4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-3-formamyl phenyl)-N-(3-(3-cyano-phenyl)-2-(E)-propenyl) sulphonamide ethyl acetate
3-(3-cyano-phenyl)-2-(E)-propylene-1-alcohol (0.7g), N-(4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-3-formamyl phenyl) sulphonamide ethyl acetate (2.0g) and triphenylphosphine (1.5g) are dissolved in the methylene dichloride (30ml); drip diethyl azodiformate (0.9ml), then at room temperature stirred 8 hours.With the reaction mixture concentrating under reduced pressure, residue is made with extra care (elutriant: hexane/ethyl acetate=1/2), obtain yellow amorphous solid title compound 2.5g (yield 94%) with silica gel column chromatography.
1H?NMR(500MHz，CDCl 3)δppm：1.36(3H，t，J＝7.0)，1.47(9H，s)，1.75-1.85(2H，m)，2.00-2.10(2H，m)，3.27(2H，m)，3.75-3.85(2H，m)，3.99(2H，s)，4.31(2H，q，J＝7.0)，4.53(2H，d，J＝7.0)，4.66(1H，m)，6.22(1H，dt，J＝16.0，7.0)，6.42(1H，d，J＝16.0)，7.01(1H，m)，7.39(1H，m)，7.45-7.60(2H，m)，7.65-7.75(2H，m)，8.32(1H，m)。
Reference example 76
4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-3-(N-methylamino formyl radical) oil of mirbane
4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-3-carboxyl oil of mirbane (3.3g) is dissolved in the methylene dichloride (50ml), at ice-cooled lower adding isobutyl chlorocarbonate (1.4ml) and triethylamine (1.4ml), under same temperature, stirred 0.5 hour, then add 40% aqueous methylamine solution (1.1ml), at room temperature stirred 3 hours.With the reaction mixture concentrating under reduced pressure, residue is made with extra care (elutriant: methylene chloride/methanol=19/1), obtain yellow amorphous solid title compound 3.5g (quantitative yield) with silica gel column chromatography.
1H?NMR(500MHz，CDCl 3)δppm：1.48(9H，s)，1.80-1.90(2H，m)，2.05-2.15(2H，m)，3.04(3H，m)，3.30-3.40(2H，m)，3.75-3.85(2H，m)，4.79(1H，m)，7.08(1H，d，J＝9.0)，8.29(1H，dd，J＝9.0，3.0)，9.07(1H，d，J＝3.0)。
Reference example 77
4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-3-(N-methylamino formyl radical) aniline
4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-3-(N-methylamino formyl radical) oil of mirbane (3.5g) is dissolved in the methyl alcohol (50ml); add palladium carbon catalyzer (0.4g), then in atmosphere of hydrogen, at room temperature stirred 1 hour.Reaction mixture is filtered, and filtrate decompression is concentrated, and residue is made with extra care (elutriant: methylene chloride/methanol=19/1), obtain yellow amorphous solid title compound 2.9g (yield 92%) with silica gel column chromatography.
1H?NMR(500MHz，CDCl 3)δppm：1.47(9H，s)，1.65-1.75(2H，m)，1.95-2.05(2H，m)，2.99(3H，m)，3.20(2H，m)，3.75-3.85(2H，m)，4.40(1H，m)，6.74(1H，dd，J＝9.0，3.0)，6.81(1H，d，J＝9.0)，7.50(1H，d，J＝3.0)。
Reference example 78
N-(4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-3-(N '-the methylamino formyl radical) phenyl) the sulphonamide ethyl acetate
4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-3-(N-methylamino formyl radical) aniline (2.9g) and pyridine (0.8ml) are dissolved in the methylene dichloride (50ml); in ice-cooled lower dropping chlorine sulphonyl ethyl acetate (1.3ml), at room temperature stirred 1 hour.With the reaction mixture concentrating under reduced pressure, residue is made with extra care (elutriant: dichloromethane/ethyl acetate=2/1), obtain faint yellow solid title compound 3.0g (yield 72%) with silica gel column chromatography.
1H?NMR(500MHz，CDCl 3)δppm：1.28(3H，t，J＝7.0)，1.48(9H，s)，1.70-1.85(2H，m)，2.00-2.15(2H，m)，3.05(3H，m)，3.29(2H，m)，3.70-3.85(2H，m)，3.95(2H，s)，4.22(2H，q，J＝7.0)，4.63(1H，m)，7.00(1H，d，J＝9.0)，7.61(1H，dd，J＝9.0，3.0)，8.27(1H，d，J＝3.0)。
Reference example 79
N-(4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-3-(N '-the methylamino formyl radical) phenyl)-N-(3-(3-cyano-phenyl)-2-(E)-propenyl) sulphonamide ethyl acetate
3-(3-cyano-phenyl)-2-(E)-propylene-1-alcohol (0.5g), N-(4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-3-(N ' methylamino formyl radical) phenyl) sulphonamide ethyl acetate (1.5g) and triphenylphosphine (1.0g) are dissolved in the methylene dichloride (40ml); at ice-cooled lower dropping diethyl azodiformate (0.6ml), then at room temperature stirred 3 hours.With the reaction mixture concentrating under reduced pressure, residue is made with extra care (elutriant: hexane/ethyl acetate=1/2), obtain colourless amorphous solid title compound 1.5g (yield 77%) with silica gel column chromatography.
1H?NMR(500MHz，CDCl 3)δppm：1.36(3H，t，J＝7.0)，1.47(9H，s)，1.75-1.85(2H，m)，2.00-2.10(2H，m)，3.01(3H，m)，3.30(2H，m)，3.70-3.80(2H，m)，3.99(2H，s)，4.32(2H，q，J＝7.0)，4.53(2H，d，J＝7.0)，4.64(1H，m)，6.22(1H，dt，J＝16.0，7.0)，6.42(1H，d，J＝16.0)，6.98(1H，m)，7.35-7.45(1H，m)，7.45-7.55(4H，m)，8.33(1H，m)。
Reference example 80
4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-3-(N, N-formyl-dimethylamino) oil of mirbane
4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-3-carboxyl oil of mirbane (3.4g) is dissolved in methylene dichloride (60ml), at ice-cooled lower adding isobutyl chlorocarbonate (1.4ml) and triethylamine (1.5ml), under same temperature, stirred 0.5 hour, add 50% dimethylamine agueous solution (1.1ml), at room temperature stirred 2 hours.With the reaction mixture concentrating under reduced pressure, residue is made with extra care (elutriant: methylene chloride/methanol=19/1), obtain faint yellow amorphous solid title compound 3.1g (yield 83%) with silica gel column chromatography.
1H?NMR(400MHz，CDCl 3)δppm：1.47(9H，s)，1.75-2.10(4H，m)，2.89(3H，s)，3.14(3H，s)，3.35-3.65(4H，m)，4.69(1H，m)，7.00(1H，d，J＝9.0)，8.20(1H，d，J＝3.0)，8.25(1H，dd，J＝9.0，3.0)。
Reference example 81
4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-3-(N, N-formyl-dimethylamino) aniline
4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-3-(N; the N-formyl-dimethylamino) oil of mirbane (3.1g) is dissolved in the methyl alcohol (30ml); add palladium carbon catalyzer (0.3g), then in atmosphere of hydrogen, at room temperature stirred 1 hour.Reaction mixture is filtered, and filtrate decompression is concentrated,, residue is made with extra care (elutriant: methylene chloride/methanol=19/1), obtain yellow amorphous solid title compound 2.8g (yield 99%) with silica gel column chromatography.
1H?NMR(400MHz，CDCl 3)δppm：1.45(9H，s)，1.55-1.95(4H，m)，2.89(3H，s)，3.09(3H，s)，3.25-3.40(2H，m)，3.50-3.65(2H，m)，4.20-4.30(1H，m)，6.61(1H，d，J＝3.0)，6.64(1H，dd，J＝9.0，3.0)，6.76(1H，d，J＝9.0)。
Reference example 82
N-(4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-3-(N ', N '-formyl-dimethylamino) phenyl) the sulphonamide ethyl acetate
4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-3-(N; the N-formyl-dimethylamino) aniline (2.8g) and pyridine (0.7ml) are dissolved in the methylene dichloride (30ml); in ice-cooled lower dropping chlorine sulphonyl ethyl acetate (1.2ml), then at room temperature stirred 1 hour.With the reaction mixture concentrating under reduced pressure, residue is made with extra care (elutriant: dichloromethane/ethyl acetate=1/1), obtain yellow amorphous solid title compound 3.3g (yield 79%) with silica gel column chromatography.
1H?NMR(400MHz，CDCl 3)δppm：1.32(3H，t，J＝7.0)，1.46(9H，s)，1.70-2.00(4H，m)，2.87(3H，s)，3.10(3H，s)，3.30-3.50(2H，m)，3.50-3.60(2H，m)，3.93(2H，s)，4.28(2H，q，J＝7.0)，4.48(1H，m)，6.91(1H，d，J＝9.0)，7.22(1H，d，J＝3.0)，7.34(1H，dd，J＝9.0，3.0)。
Reference example 83
N-(4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-3-(N ', N '-formyl-dimethylamino) phenyl)-N-(3-(3-cyano-phenyl)-2-(E)-propenyl) sulphonamide ethyl acetate
3-(3-cyano-phenyl)-2-(E)-propylene-1-alcohol (0.5g), N-(4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-3-(N '; N '-formyl-dimethylamino) phenyl) sulphonamide ethyl acetate (1.5g) and triphenylphosphine (1.0g) are dissolved in the methylene dichloride (30ml); at ice-cooled lower dropping diethyl azodiformate (0.6ml), then at room temperature stirred 3 hours.With the reaction mixture concentrating under reduced pressure, residue is made with extra care (elutriant: hexane/ethyl acetate=1/2), obtain colourless amorphous solid title compound 1.7g (yield 88%) with silica gel column chromatography.
1H?NMR(400MHz，CDCl 3)δppm：1.34(3H，t，J＝7.0)，1.46(9H，s)，1.75-2.00(4H，m)，2.83(3H，s)，3.10(3H，s)，3.30-3.60(4H，m)，3.95-4.05(2H，m)，4.30(2H，q，J＝7.0)，4.47(2H，d，J＝7.0)，4.52(1H，m)，6.23(1H，dt，J＝16.0，7.0)，6.42(1H，d，J＝16.0)，6.92(1H，m)，7.35-7.55(6H，m)。
Reference example 84
5-cyano-2-hydroxy-phenyl aldehyde
4-cyanophenol (25.0g) is dissolved in the trifluoroacetic acid (150ml), adds vulkacit H (50.0g), stirs 9 hours at 100 ℃.Add sulfuric acid (50ml) and water (300ml) after reaction mixture is cooled to room temperature, then at room temperature stirred 1 hour.Reaction mixture dichloromethane extraction, extraction liquid be water and saturated common salt water washing successively, the organic layer anhydrous magnesium sulfate drying.Decompression steams solvent after filtering, and the gained residue is made with extra care (elutriant: ethyl acetate/dichloromethane=1/19), obtain colorless solid title compound 4.3g (yield 13%) with silica gel column chromatography.
1H?NMR(400MHz，CDCl 3)δppm：7.11(1H，d，J＝9.0)，7.78(1H，dd，J＝9.0，2.0)，7.94(1H，d，J＝2.0)，9.93(1H，s)。
Reference example 85
5-cyano-2-hydroxy-phenylacrolein
The positive phosphorus summarized of 5-cyano-2-hydroxy-phenyl aldehyde (4.3g) and triphenyl (9.4g) is dissolved in the toluene (150ml), stirs 2 hours at 70 ℃.With the reaction mixture concentrating under reduced pressure, residue is made with extra care (elutriant: ethyl acetate/dichloromethane=1/3), obtain colorless solid title compound 2.3g (yield 44%) with silica gel column chromatography.
1H?NMR(400MHz，DMSO-d 6)δppm：6.98(1H，dd，J＝16.0，8.0)，7.08(1H，d，J＝9.0)，7.73(1H，d，J＝9.0)，7.83(1H，d，J＝16.0)，8.22(1H，s)，9.67(1H，d，J＝8.0)。
Reference example 86
5-cyano group-2-methoxymethoxy phenylacrolein
5-cyano-2-hydroxy-phenylacrolein (2.3g) is dissolved in the DMF (25ml), at ice-cooled lower adding methoxymethyl chlorine (1.5ml) and triethylamine (2.8ml), at room temperature stirs 1 hour.The saturated common salt water washing of reaction mixture ethyl acetate extraction, extraction liquid, the organic layer anhydrous magnesium sulfate drying.Decompression steams solvent after filtering, and obtains colorless solid title compound 2.8g (yield 98%).
1H?NMR(400MHz，CDCl 3)δppm：3.52(3H，s)，5.36(2H，s)，6.80(1H，dd，J＝16.0，8.0)，7.30(1H，d，J＝9.0)，7.66(1H，dd，J＝9.0，2.0)，7.75(1H，d，J＝16.0)，7.84(1H，d，J＝2.0)，9.74(1H，d，J＝8.0)。
Reference example 87
3-(5-cyano group-methoxymethoxy phenyl)-2-(E)-propylene-1-alcohol
5-cyano group-2-methoxymethoxy phenylacrolein (2.8g) is dissolved in the mixed solvent of methylene dichloride (20ml) and ethanol (40ml), at ice-cooled lower adding Cerium II Chloride (1.7g), under same temperature, stirred 0.5 hour, then add sodium borohydride (0.9g), under same temperature, stirred 2 hours again.Add saturated aqueous ammonium chloride in reaction mixture, then use dichloromethane extraction, extraction liquid is water and saturated common salt water washing successively, the organic layer anhydrous magnesium sulfate drying.Decompression steams solvent after filtering, and residue is made with extra care (elutriant: hexane/ethyl acetate=1/1), obtain yellow oily title compound 2.6g (yield 93%) with silica gel column chromatography.
1H?NMR(500MHz，CDCl 3)δppm：3.49(3H，s)，4.37(2H，d，J＝5.0)，5.27(2H，s)，6.41(1H，dt，J＝16.0，5.0)，6.90(1H，d，J＝16.0)，7.18(1H，d，J＝9.0)，7.49(1H，dd，J＝9.0，2.0)，7.72(1H，d，J＝2.0)。
Reference example 88
N-(4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-3-chloro-phenyl-)-N-(3-(5-cyano group-methoxymethoxy phenyl)-2-(E)-propenyl) sulphonamide ethyl acetate
3-(5-cyano group-methoxymethoxy phenyl)-2-(E)-propylene-1-alcohol (0.6g), N-(4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-3-chloro-phenyl-) sulphonamide ethyl acetate (1.3g) and triphenylphosphine (0.9g) are dissolved in the methylene dichloride (40ml), at ice-cooled lower adding diethyl azodiformate (0.6ml), at room temperature stirred 1.5 hours.With the reaction mixture concentrating under reduced pressure, residue is made with extra care (elutriant: dichloromethane/ethyl acetate=9/1), obtain yellow amorphous solid title compound 1.4g (yield 74%) with silica gel column chromatography.
1H?NMR(500MHz，CDCl 3)δppm：1.36(3H，t，J＝7.0)，1.47(9H，s)，1.75-1.85(2H，m)，1.85-1.95(2H，m)，3.40-3.50(2H，m)，3.44(3H，s)，3.55-3.65(2H，m)，3.99(2H，s)，4.31(2H，q，J＝7.0)，4.48(2H，d，J＝7.0)，4.55(1H，m)，5.23(2H，s)，6.17(1H，dt，J＝16.0，7.0)，6.70(1H，d，J＝16.0)，6.94(1H，d，J＝9.0)，7.13(1H，d，J＝9.0)，7.34(1H，dd，J＝9.0，3.0)，7.47(1H，dd，J＝9.0，2.0)，7.55(1H，d，J＝3.0)，7.61(1H，d，J＝2.0)。
Reference example 89
3-chloro-5-NITROSALICYLIC ACID methyl esters
3-chloro-salicylic acid (4.5g) is dissolved in the mixed solvent of methyl alcohol (10ml) and benzene (40ml), and then the hexane solution (20.0ml) at ice-cooled lower adding 2M trimethyl silyl diazomethane at room temperature stirred 2 hours.With the reaction mixture concentrating under reduced pressure, the gained colourless oily mater joins in the mixing solutions of 69% nitric acid (15ml) and the vitriol oil (15ml), then at room temperature stirs 0.5 hour.Reaction mixture is poured in the frozen water, uses ethyl acetate extraction, extraction liquid is water and saturated common salt water washing successively, the organic layer anhydrous magnesium sulfate drying.Decompression steams solvent after filtering, and adds hexane in the gained yellow solid, obtains yellow solid title compound 2.4g (yield 39%) after the filtration.
1H?NMR(500MHz，CDCl 3)δppm：4.07(3H，s)，8.47(1H，d，J＝3.0)，8.72(1H，d，J＝3.0)。
Reference example 90
4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-3-chloro-5-methoxycarbonyl oil of mirbane
1-tertbutyloxycarbonyl-4-hydroxy piperidine (6.3g), 3-chloro-5-NITROSALICYLIC ACID methyl esters (2.4g) and triphenylphosphine (10.8g) are dissolved in the methylene dichloride (100ml), add diethyl azodiformate (6.6ml), at room temperature stirred 4 hours.With the reaction mixture concentrating under reduced pressure, residue is made with extra care (elutriant: hexane/ethyl acetate=4/1), obtain pink solid title compound 3.4g (yield 79%) with silica gel column chromatography.
1H?NMR(500MHz，CDCl 3)δppm：1.47(9H，s)，1.75-1.85(2H，m)，1.85-1.95(2H，m)，3.11(2H，m)，3.85-3.95(2H，m)，3.97(3H，s)，4.44(1H，m)，8.43(1H，d，J＝3.0)，8.56(1H，d，J＝3.0)。
Reference example 91
4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-5-carboxyl-3-chloronitrobenzene
4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-3-chloro-5-methoxycarbonyl oil of mirbane (3.4g) is dissolved in the concentrated hydrochloric acid (30ml), stirs 16 hours at 75 ℃.With the reaction mixture concentrating under reduced pressure, the gained colorless solid is dissolved in the mixed solvent of water (15ml) and acetone (15ml), at ice-cooled lower adding sodium bicarbonate (1.6g) and tert-Butyl dicarbonate (2.2g), then stirred 1 hour at 40 ℃.Reaction mixture ethyl acetate extraction, extraction liquid are used 0.5M hydrochloric acid, water and saturated common salt water washing, organic layer anhydrous magnesium sulfate drying successively.Decompression steams solvent after filtering, and adds hexane in the gained faint yellow solid, obtains faint yellow solid title compound 2.6g (yield 79%) after the filtration.
1H?NMR(500MHz，CDCl 3)δppm：1.48(9H，s)，1.85-1.95(2H，m)，1.95-2.05(2H，m)，3.16(2H，m)，3.90-4.00(2H，m)，4.54(1H，m)，8.45(1H，d，J＝3.0)，8.70(1H，d，J＝3.0)。
Reference example 92
4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-5-formamyl-3-chloronitrobenzene
4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-5-carboxyl-3-chloronitrobenzene (2.6g) is dissolved in the methylene dichloride (80ml), at ice-cooled lower adding isobutyl chlorocarbonate (1.0ml) and triethylamine (1.1ml), under same temperature, stirred 0.5 hour, then add 28% ammoniacal liquor (0.5ml), at room temperature stirred 1 hour.With the reaction mixture concentrating under reduced pressure, residue is made with extra care (elutriant: methylene chloride/methanol=19/1), obtain faint yellow amorphous solid title compound 2.2g (yield 84%) with silica gel column chromatography.
1H?NMR(500MHz，CDCl 3)δppm：1.47(9H，s)，1.75-1.85(2H，m)，2.00-2.10(2H，m)，2.85(2H，m)，4.05-4.15(2H，m)，4.51(1H，m)，8.42(1H，d，J＝3.0)，8.79(1H，d，J＝3.0)。
Reference example 93
4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-5-formamyl-3-chloroaniline
4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-5-formamyl-3-chloronitrobenzene (2.2g) is dissolved in the acetic acid (100ml), adds glass putty (9.9g), then at room temperature stirs 11 hours.Reaction mixture filters by Celite (registered trademark), filtrate decompression is concentrated, and the gained faint yellow solid is dissolved in the wet chemical, then uses ethyl acetate extraction, extraction liquid is water and saturated common salt water washing successively, the organic layer anhydrous magnesium sulfate drying.Decompression steams solvent after filtering, and obtains yellow amorphous solid title compound 1.7g (yield 83%).
1H?NMR(500MHz，CDCl 3)δppm：1.46(9H，s)，1.65-1.75(2H，m)，1.95-2.05(2H，m)，2.77(2H，m)，3.70-3.80(2H，m)，4.17(1H，m)，6.84(1H，d，J＝3.0)，7.19(1H，d，J＝3.0)。
Reference example 94
N-(4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-5-formamyl-3-chloro-phenyl-) sulphonamide ethyl acetate
4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-5-formamyl-3-chloroaniline (1.7g); be dissolved in the methylene dichloride (30ml); add pyridine (0.7ml), then in ice-cooled lower dropping chlorine sulphonyl ethyl acetate (0.7ml), at room temperature stirred 1 hour.With the reaction mixture concentrating under reduced pressure, residue is made with extra care (elutriant: methylene chloride/methanol=1/1), obtain faint yellow solid title compound 1.2g (yield 48%) with silica gel column chromatography.
1H?NMR(500MHz，DMSO-d 6)δppm：1.17(3H，t，J＝7.0)，1.40(9H，s)，1.55-1.65(2H，m)，1.80-1.90(2H，m)，2.95-3.05(2H，m)，3.70-3.80(2H，m)，4.10(2H，q，J＝7.0)，4.21(1H，m)，4.27(2H，s)，7.28(1H，d，J＝3.0)，7.36(1H，d，J＝3.0)。
Reference example 95
N-(4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-5-formamyl-3-chloro-phenyl-)-N-(3-(3-cyano-phenyl)-2-(E)-propenyl) sulphonamide ethyl acetate
3-(3-cyano-phenyl)-2-(E)-propylene-1-alcohol (0.4g), N-(4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-5-formamyl-3-chloro-phenyl-) sulphonamide ethyl acetate (1.2g) and triphenylphosphine (0.8g) are dissolved in the mixed solvent of methylene dichloride (50ml) and tetrahydrofuran (THF) (20ml); at ice-cooled lower adding diethyl azodiformate (0.5ml), at room temperature stirred 1 hour.With the reaction mixture concentrating under reduced pressure, residue is made with extra care (elutriant: dichloromethane/ethyl acetate=3/2), obtain colourless amorphous solid title compound 1.5g (quantitative yield) with silica gel column chromatography.
1H?NMR(400MHz，CDCl 3)δppm：1.35(3H，t，J＝7.0)，1.46(9H，s)，1.65-1.80(2H，m)，1.95-2.05(2H，m)，2.79(2H，m)，4.00(2H，s)，4.00-4.15(2H，m)，4.31(2H，q，J＝7.0)，4.38(1H，m)，4.53(2H，d，J＝7.0)，6.21(1H，dt，J＝16.0，7.0)，6.46(1H，d，J＝16.0)，7.23(1H，m)，7.41(1H，m)，7.50-7.60(3H，m)，8.03(1H，m)。
Reference example 96
3-methyl-5-nitro wintergreen oil
3-cresotinic acid (5.1g) is dissolved in the mixed solvent of methyl alcohol (10ml) and benzene (40ml), and then the hexane solution (25.0ml) at ice-cooled lower adding 2M trimethyl silyl diazomethane at room temperature stirred 1 hour.With the reaction mixture concentrating under reduced pressure, the gained colourless oily mater joins in the mixing solutions of 69% nitric acid (15ml) and the vitriol oil (15ml), then at room temperature stirs 1 hour.Reaction mixture is poured in the frozen water, uses ethyl acetate extraction, extraction liquid is water and saturated common salt water washing successively, the organic layer anhydrous magnesium sulfate drying.Decompression steams solvent after filtering, and residue is made with extra care (elutriant: hexane/ethyl acetate=2/1), add hexane in the gained yellow solid, obtain faint yellow solid title compound 1.8g (yield 25%) after the filtration with silica gel column chromatography.
1H?NMR(500MHz，CDCl 3)δppm：2.35(3H，s)，4.03(3H，s)，8.21(1H，d，J＝3.0)，8.66(1H，d，J＝3.0)。
Reference example 97
4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-3-methoxycarbonyl-5-methyl oil of mirbane
1-tertbutyloxycarbonyl-4-hydroxy piperidine (4.2g), 3-methyl-5-nitro wintergreen oil (1.8g) and triphenylphosphine (6.8g) are dissolved in the methylene dichloride (100ml), add diethyl azodiformate (4.1ml), at room temperature stirred 3 hours.With the reaction mixture concentrating under reduced pressure, residue is made with extra care (elutriant: hexane/ethyl acetate=4/1), obtain pink oily title compound 3.1g (yield 91%) with silica gel column chromatography.
1H?NMR(400MHz，CDCl 3)δppm：1.47(9H，s)，1.65-1.75(2H，m)，1.85-1.95(2H，m)，2.39(3H，s)，2.97(2H，m)，3.90-4.00(2H，m)，3.95(3H，s)，4.16(1H，m)，8.22(1H，d，J＝3.0)，8.52(1H，d，J＝3.0)。
Reference example 98
4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-3-carboxyl-5-methyl oil of mirbane
4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-3-methoxycarbonyl-5-methyl oil of mirbane (4.0g) is dissolved in the concentrated hydrochloric acid (40ml), stirs 7 hours at 75 ℃.With the reaction mixture concentrating under reduced pressure, the gained white solid is dissolved in the mixed solvent of water (20ml) and acetone (20ml), at ice-cooled lower sodium bicarbonate (1.9g) and tert-Butyl dicarbonate (2.7g), then stirred 2 hours at 40 ℃.Reaction mixture ethyl acetate extraction, extraction liquid are used 0.5M hydrochloric acid, water and saturated common salt water washing, organic layer anhydrous magnesium sulfate drying successively.Decompression steams solvent after filtering, and adds hexane in the gained faint yellow solid, obtains faint yellow solid title compound 3.6g (yield 79%) after the filtration.
1H?NMR(400MHz，CDCl 3)δppm：1.47(9H，s)，1.70-1.85(2H，m)，1.90-2.05(2H，m)，2.43(3H，s)，2.95(2H，m)，4.00-4.10(2H，m)，4.26(1H，m)，8.26(1H，d，J＝3.0)，8.69(1H，d，J＝3.0)。
Reference example 99
4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-3-formamyl-5-methyl oil of mirbane
4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-3-carboxyl-5-methyl oil of mirbane (3.6g) is dissolved in the methylene dichloride (60ml), at ice-cooled lower adding isobutyl chlorocarbonate (1.4ml) and triethylamine (1.6ml), under same temperature, stirred 0.5 hour, then add 28% ammoniacal liquor (0.7ml), at room temperature stirred 1.5 hours.With the reaction mixture concentrating under reduced pressure, residue is made with extra care (elutriant: methylene chloride/methanol=19/1), obtain yellow oily title compound 3.9g (quantitative yield) with silica gel column chromatography.
1H?NMR(500MHz，CDCl 3)δppm：1.46(9H，s)，1.70-1.80(2H，m)，1.90-2.00(2H，m)，2.43(3H，s)，2.79(2H，m)，4.05-4.15(2H，m)，4.17(1H，m)，8.20(1H，d，J＝3.0)，8.66(1H，d，J＝3.0)。
Reference example 100
4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-3-formamyl-5-monomethylaniline
4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-3-formamyl-5-methyl oil of mirbane (3.9g) is dissolved in the methyl alcohol (100ml), adds palladium carbon catalyzer (0.5g), then at room temperature stirs in atmosphere of hydrogen 1.5 hours.Reaction mixture is filtered, and filtrate decompression is concentrated, obtains blackish green amorphous solid title compound 3.5g (yield 97%).
1H?NMR(500MHz，CDCl 3)δppm：1.46(9H，s)，1.60-1.70(2H，m)，1.90-2.00(2H，m)，2.23(3H，s)，2.71(2H，m)，3.62(2H，m)，3.80-3.90(1H，m)，6.65(1H，d，J＝3.0)，7.11(1H，d，J＝3.0)。
Reference example 101
N-(4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-3-formamyl-5-aminomethyl phenyl) sulphonamide ethyl acetate
4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-3-formamyl-5-monomethylaniline (3.5g) and pyridine (1.0ml) are dissolved in methylene dichloride (80ml); in ice-cooled lower dropping chlorine sulphonyl ethyl acetate (1.6ml), then at room temperature stirred 0.5 hour.With the reaction mixture concentrating under reduced pressure, residue is made with extra care (elutriant: methylene chloride/methanol=19/1), obtain faint yellow solid title compound 2.6g (yield 51%) with silica gel column chromatography.
1H?NMR(500MHz，CDCl 3)δppm：1.31(3H，t，J＝7.0)，1.46(9H，s)，1.65-1.75(2H，m)，1.90-2.00(2H，m)，2.33(3H，s)，2.74(2H，m)，3.90-4.00(1H，m)，3.97(2H，s)，4.00-4.15(2H，m)，4.27(2H，q，J＝7.0)，7.44(1H，d，J＝3.0)，7.72(1H，d，J＝3.0)。
Reference example 102
N-(4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-3-formamyl-5-aminomethyl phenyl)-N-(3-(3-cyano-phenyl)-2-(E)-propenyl) sulphonamide ethyl acetate
3-(3-cyano-phenyl)-2-(E)-propylene-1-alcohol (0.8g), N-(4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-3-formamyl-5-aminomethyl phenyl) sulphonamide ethyl acetate (2.6g) and triphenylphosphine (1.7g) are dissolved in the mixed solvent of methylene dichloride (50ml) and tetrahydrofuran (THF) (50ml); at ice-cooled lower adding diethyl azodiformate (1.0ml), then at room temperature stirred 1.5 hours.With the reaction mixture concentrating under reduced pressure, residue is made with extra care (elutriant: hexane/ethyl acetate=1/2), obtain yellow amorphous solid title compound 3.2g (yield 96%) with silica gel column chromatography.
1H?NMR(500MHz，CDCl 3)δppm：1.35(3H，t，J＝7.0)，1.46(9H，s)，1.65-1.75(2H，m)，1.85-1.95(2H，m)，2.32(3H，s)，2.73(2H，m)，3.95-4.05(1H，m)，4.00(2H，s)，4.05-4.15(2H，m)，4.31(2H，q，J＝7.0)，4.52(2H，d，J＝7.0)，6.22(1H，dt，J＝16.0，7.0)，6.44(1H，d，J＝16.0)，7.22(1H，m)，7.40(1H，m)，7.50-7.60(3H，m)，7.91(1H，m)。
Reference example 103
2,6-, two fluoro-4-nitrophenols
2,6-difluorophenol (2.00g) is dissolved in the acetic acid (20ml), at ice-cooled lower dropping 60% nitric acid (1.20ml), then at room temperature stirs 1 hour.Reaction mixture is poured in the frozen water, uses ethyl acetate extraction, extraction liquid saturated common salt water washing, organic layer anhydrous magnesium sulfate drying.Decompression steams solvent after filtering, and residue is made with extra care (elutriant: hexane/ethyl acetate=3/1-2/1), obtain faint yellow solid title compound 1.37g (yield 51%) with silica gel column chromatography.
1H?NMR(400MHz，CDCl 3)δppm：7.95(2H，m)。
Reference example 104
4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-3, the 5-difluoro nitrobenzene
1-tertbutyloxycarbonyl-4-hydroxy piperidine (1.73g), 2,6-two fluoro-4-nitrophenols (1.37g) and triphenylphosphine (2.67g) are dissolved in the methylene dichloride (30ml).At ice-cooled lower dropping diethyl azodiformate (1.5ml), then at room temperature stirred 9 hours.With the reaction mixture concentrating under reduced pressure, residue is made with extra care (elutriant: hexane/ethyl acetate=6/1), obtain faint yellow solid title compound 2.13g (yield 76%) with silica gel column chromatography.
1H?NMR(400MHz，CDCl 3)δppm：1.47(9H，s)，1.77-1.85(2H，m)，1.89-1.96(2H，m)，3.35(2H，m)，3.72(2H，m)，4.62(1H，m)，7.87(2H，m)。
Reference example 105
4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-3, the 5-difluoroaniline
4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-3,5-difluoro nitrobenzene (2.13g) is dissolved in the ethanol (40ml), adds palladium carbon catalyzer (0.20g), then at room temperature stirs in atmosphere of hydrogen 1 hour.Reaction mixture is filtered, and filtrate decompression is concentrated, and residue is made with extra care (elutriant: hexane/ethyl acetate=2/1), obtain colorless solid title compound 1.70g (yield 87%) with silica gel column chromatography.
1H?NMR(400MHz，CDCl 3)δppm：1.46(9H，s)，1.72-1.78(2H，m)，1.83-1.89(2H，m)，3.23(2H，m)，3.77(2H，m)，4.11(1H，m)，6.21(2H，m)。
Reference example 106
N-(4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-3,6-difluorophenyl) sulphonamide ethyl acetate
4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-3,5-difluoroaniline (1.70g) and pyridine (0.84ml) are dissolved in the methylene dichloride (30ml), in ice-cooled lower dropping chlorine sulphonyl ethyl acetate (0.76ml), at room temperature stirred 1.5 hours.In reaction mixture, add entry, use ethyl acetate extraction, extraction liquid saturated common salt water washing, organic layer anhydrous magnesium sulfate drying.Decompression steams solvent after filtering, and residue is made with extra care (elutriant: hexane/ethyl acetate=2/1), obtain yellow oily title compound 2.48g (quantitative yield) with silica gel column chromatography.
1H?NMR(400MHz，CDCl 3)δppm：1.34(3H，t，J＝7.0)，1.47(9H，s)，1.72-1.82(2H，m)，1.83-1.93(2H，m)，3.28(2H，m)，3.75(2H，m)，3.95(2H，s)，4.30(2H，q，J＝7.0)，4.31(1H，m)，6.95(2H，m)。
Reference example 107
N-(4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-3,6-difluorophenyl)-N-(3-(3-cyano-phenyl)-2-(E)-propenyl) sulphonamide ethyl acetate
3-(3-cyano-phenyl)-2-(E)-propylene-1-alcohol (0.52g), N-(4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-3, the 6-difluorophenyl) sulphonamide ethyl acetate (1.55g) and triphenylphosphine (1.02g) are dissolved in the methylene dichloride (30ml), at ice-cooled lower dropping diethyl azodiformate (0.60ml), then under same temperature, stirred 1 hour.With the reaction mixture concentrating under reduced pressure, residue is made with extra care (elutriant: hexane/ethyl acetate=2/1), obtain colourless amorphous solid title compound 1.82g (yield 91%) with silica gel column chromatography.
1H?NMR(400MHz，CDCl 3)δppm：1.36(3H，t，J＝7.0)，1.46(9H，s)，1.72-1.82(2H，m)，1.83-1.93(2H，m)，3.29(2H，m)，3.73(2H，m)，3.99(2H，s)，4.31(2H，q，J＝7.0)，4.37(1H，m)，4.47(2H，d，J＝6.5)，6.20(1H，dt，J＝16.0，6.5)，6.43(1H，d，J＝16.0)，7.12(2H，m)，7.41(1H，t，J＝7.5)，7.53(1H，d，J＝7.5)，7.54(1H，d，J＝7.5)，7.57(1H，s)。
Reference example 108
4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-3, the 5-dichloronitrobenzene
1-tertbutyloxycarbonyl-4-hydroxy piperidine (677mg), 2,6-two chloro-4-nitrophenolss (700mg) and triphenylphosphine (1150mg) are dissolved in the methylene dichloride (40ml), at ice-cooled lower dropping diethyl azodiformate (0.67ml), at room temperature stirred 2 hours.With the reaction mixture concentrating under reduced pressure, residue is made with extra care (elutriant: hexane/ethyl acetate=6/1), obtain colorless solid title compound 950mg (yield 72%) with silica gel column chromatography.
1H?NMR(400MHz，CDCl 3)δppm：1.48(9H，s)，1.85-2.00(4H，m)，3.20(2H，m)，3.91(2H，m)，4.59(1H，m)，8.23(2H，s)。
Reference example 109
4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-3, the 5-dichlorphenamide bulk powder
4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-3,5-dichloronitrobenzene (1.95g) is dissolved in the acetic acid (50ml), at room temperature divides 5 times and adds zinc powder (11.10g), then stirs 6 hours at 50 ℃.Reaction mixture is filtered, and filtrate decompression is concentrated, and adding ethyl acetate and water extract extraction liquid saturated common salt water washing in the residue.The organic layer anhydrous magnesium sulfate drying.Decompression steams solvent after filtering, and the gained residue is made with extra care (elutriant: hexane/ethyl acetate=3/1), obtain colorless solid title compound 1.40g (yield 78%) with silica gel column chromatography.
1H?NMR(500MHz，CDCl 3)δppm：1.47(9H，s)，1.80-1.95(4H，m)，3.09(2H，m)，3.92(2H，m)，4.22(1H，m)，6.61(2H，s)。
Reference example 110
N-(4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-3,5-dichlorophenyl) sulphonamide ethyl acetate
4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-3,5-dichlorphenamide bulk powder (1.40g) and pyridine (0.63ml) are dissolved in methylene dichloride (30ml), in ice-cooled lower dropping chlorine sulphonyl ethyl acetate (0.57ml), at room temperature stirred 1.5 hours.In reaction mixture, add ethyl acetate and water, extract extraction liquid saturated common salt water washing, organic layer anhydrous magnesium sulfate drying.Decompression steams solvent after filtering, and the gained residue is made with extra care (elutriant: hexane/ethyl acetate=2/1), obtain yellow amorphous solid title compound 1.8g (yield 95%) with silica gel column chromatography.
1H?NMR(400MHz，CDCl 3)δppm：1.34(3H，t，J＝7.0)，1.47(9H，s)，1.80-2.00(4H，m)，3.14(2H，m)，3.92(2H，m)，3.96(2H，s)，4.30(2H，q，J＝7.0)，4.37(1H，m)，7.33(2H，s)。
Reference example 111
N-(4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-3,5-dichlorophenyl)-N-(3-(3-cyano-phenyl)-2-(E)-propenyl) sulphonamide ethyl acetate
3-(3-cyano-phenyl)-2-(E)-propylene-1-alcohol (0.59g), N-(4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-3, the 5-dichlorophenyl) sulphonamide ethyl acetate (1.89g) and triphenylphosphine (1.16g) are dissolved in the methylene dichloride (30ml), at ice-cooled lower dropping diethyl azodiformate (0.68ml), then under same temperature, stirred 4 hours.With the reaction mixture concentrating under reduced pressure, residue is made with extra care (elutriant: hexane/ethyl acetate=3/1), obtain colourless amorphous solid title compound 2.06g (yield 86%) with silica gel column chromatography.
1H?NMR(400MHz，CDCl 3)δppm：1.36(3H，t，J＝7.0)，1.47(9H，s)，1.80-2.00(4H，m)，3.15(2H，m)，3.90(2H，m)，4.00(2H，s)，4.31(2H，q，J＝7.0)，4.41(1H，m)，4.47(2H，d，J＝6.5)，6.20(1H，dt，J＝16.0，6.5)，6.44(1H，d，J＝16.0)，7.42(1H，t，J＝8.0)，7.47(2H，s)，7.53(2H，m)，7.58(1H，s)。
Reference example 112
4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-3, the 5-dimethyl nitrobenzene
1-tertbutyloxycarbonyl-4-hydroxy piperidine (2.40g), 2,6-dimethyl-4-nitrophenols (1.50g) and triphenylphosphine (3.06g) are dissolved in the methylene dichloride (60ml), at ice-cooled lower dropping diethyl azodiformate (1.80ml), then at room temperature stirred 19 hours.With the reaction mixture concentrating under reduced pressure, residue is made with extra care (elutriant: hexane/ethyl acetate=5/1), obtain colorless solid title compound 2.25g (yield 71%) with silica gel column chromatography.
1H?NMR(500MHz，CDCl 3)δppm：1.48(9H，s)，1.73(2H，m)，1.93(2H，m)，2.35(6H，s)，2.93(2H，m)，4.00-4.10(3H，m)，7.92(2H，s)。
Reference example 113
4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-3.5-xylidine
4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-3,5-dimethyl nitrobenzene (2.24g) is dissolved in the mixed solvent of ethanol (30ml) and tetrahydrofuran (THF) (10ml), add palladium carbon catalyzer (0.20g), then in atmosphere of hydrogen, at room temperature stirred 1 hour.Reaction mixture is filtered, and filtrate decompression is concentrated, and residue is made with extra care (elutriant: hexane/ethyl acetate=2/1), obtain light red solid title compound 1.94g (yield 95%) with silica gel column chromatography.
1H?NMR(500MHz，CDCl 3)δppm：1.47(9H，s)，1.66(2H，m)，1.92(2H，m)，2.19(6H，s)，2.86(2H，m)，3.79(1H，m)，4.02(2H，m)，6.36(2H，s)。
Reference example 114
N-(4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-3,5-3,5-dimethylphenyl) sulphonamide ethyl acetate
4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-3,5-xylidine (1.94g) and pyridine (0.98ml) are dissolved in the methylene dichloride (30ml), in ice-cooled lower dropping chlorine sulphonyl ethyl acetate (0.97ml), then at room temperature stirred 14 hours.In reaction mixture, add ethyl acetate and water, extract extraction liquid saturated common salt water washing, organic layer anhydrous magnesium sulfate drying.Decompression steams solvent after filtering, and the gained residue is made with extra care (elutriant: hexane/ethyl acetate=2/1), obtain faint yellow solid title compound 2.00g (yield 70%) with silica gel column chromatography.
1H?NMR(400MHz，CDCl 3)δppm：1.33(3H，t，J＝7.0)，1.47(9H，s)，1.69(2H，m)，1.91(2H，m)，2.26(6H，s)，2.89(2H，m)，3.90(1H，m)，3.93(2H，s)，4.03(2H，m)，4.29(2H，q，J＝7.0)，6.98(2H，s)。
Reference example 115
N-(4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-3,5-3,5-dimethylphenyl)-N-(3-(3-cyano-phenyl)-2-(E)-propenyl) sulphonamide ethyl acetate
3-(3-cyano-phenyl)-2-(E)-propylene-1-alcohol (0.55g), N-(4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-3, the 5-3,5-dimethylphenyl) sulphonamide ethyl acetate (1.5g) and triphenylphosphine (1.08g) are dissolved in the methylene dichloride (20ml), at ice-cooled lower dropping diethyl azodiformate (0.63ml), then under same temperature, stirred 1.5 hours.With the reaction mixture concentrating under reduced pressure, residue is made with extra care (elutriant: hexane/ethyl acetate=2/1), obtain colourless amorphous solid title compound 1.75g (yield 90%) with silica gel column chromatography.
1H?NMR(400MHz，CDCl 3)δppm：1.36(3H，t，J＝7.0)，1.47(9H，s)，1.70(2H，m)，1.91(2H，m)，2.26(6H，s)，2.90(2H，m)，3.93(1H，m)，3.99(2H，s)，4.00(2H，m)，4.30(2H，q，J＝7.0)，4.47(2H，d，J＝6.5)，6.23(1H，dt，J＝16.0，6.5)，6.42(1H，d，J＝16.0)，7.11(2H，s)，7.40(1H，t，J＝8.0)，7.52(2H，m)，7.56(1H，s)。
Reference example 116
4-(N-(4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen) phenyl)-N-(3-(3-cyano-phenyl)-2-(E)-propenyl) amino) ethyl butyrate
3-(3-(N-(4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen) phenyl) amino)-1-(E)-propenyl) benzonitrile (2.00g) is dissolved in N, in the dinethylformamide (40ml), divide 5 times and add salt of wormwood (6.50g) and bromo-butyric acid ethyl ester (5.00ml), stirred 16 hours at 140 ℃.In reaction mixture, add entry, use ethyl acetate extraction, extraction liquid saturated common salt water washing, organic layer anhydrous magnesium sulfate drying.Decompression steams solvent after filtering, and residue is made with extra care (elutriant: hexane/ethyl acetate=2/1), obtain yellow oily title compound 1.20g (yield 48%) with silica gel column chromatography.
1H?NMR(400MHz，CDCl 3)δppm：1.25(3H，t，J＝7.0)，1.46(9H，s)，1.65-1.75(2H，m)，1.80-2.00(4H，m)，2.36(2H，t，J＝7.0)，3.20-3.35(4H，m)，3.65-3.75(2H，m)，4.02(2H，d，J＝5.0)，4.13(2H，q，J＝7.0)，4.27(1H，m)，6.29(1H，dt，J＝16.0，5.0)，6.47(1H，d，J＝16.0)，6.70(2H，d，J＝9.0)，6.84(2H，d，J＝9.0)，7.39(1H，t，J＝8.0)，7.49(1H，d，J＝8.0)，7.54(1H，d，J＝8.0)，7.61(1H，s)。
Reference example 117
3-(3-cyano-phenyl)-2-fluoro-2-(Z)-propylene-1-alcohol
According to J.Organomet.Chem. 332The 2-diethyl phosphonyl (diethul phosphono) that 1 (1987) described method is synthesized-2-gifblaar poison (4.35g) is dissolved in the tetrahydrofuran (THF) (90ml); under-78 ℃ of stirrings, drip the hexane solution (28ml) of 1.6M butyllithium, under same temperature, stirred 1 hour.Drip tetrahydrofuran (THF) (10ml) solution of 3-cyanobenzaldehyde (2.66g) with 10 minutes in the reaction mixture, stirred 3 hours at-78 ℃, then be warming up to 0 ℃.Add entry (40ml) in reaction mixture, water layer is separated, organic layer extracts 2 times with saturated sodium bicarbonate aqueous solution.Water layer is merged, with the pH regulator to 4 of the vitriol oil with solution, then with methyl tertiary butyl ether extraction 5 times, extraction liquid anhydrous sodium sulfate drying.After the filtration that filtrate decompression is concentrated, obtain white solid midbody compound (3.47g).
Then, resulting midbody compound (1.15g) and triethylamine (0.92ml) are dissolved in the methylene dichloride (10ml), under ice-cooled, under agitation add Vinyl chloroformate (0.63ml), at room temperature stirred 15 minutes.Decompression steams solvent, adds ethyl acetate (10ml) in residue, and the elimination insolubles is then concentrated with filtrate decompression.Residue is dissolved in the tetrahydrofuran (THF) (10ml), under agitation adds sodium borohydride aqueous solution (0.45g is dissolved in the 5ml water) under ice-cooled, at room temperature stirs 18 hours.In reaction mixture, add saturated aqueous ammonium chloride, then with methyl tertiary butyl ether extraction 3 times, extraction liquid saturated common salt water washing, organic layer anhydrous sodium sulfate drying.Decompression steams solvent after filtering, and residue is made with extra care (elutriant: hexane/ethyl acetate=3/2), obtain colorless solid title compound 0.33g (yield 31%) with silica gel column chromatography.
1H?NMR(500MHz，CDCl 3)δppm：4.32(2H，dd，J＝12.5，5.5)，5.82(1H，d，J＝37.5)，7.45(1H，t，J＝8.0)，7.53(1H，d，J＝8.0)，7.70(1H，d，J＝8.0)，7.81(1H，s)。
Reference example 118
N-(4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen) phenyl)-N-(3-(3-cyano-phenyl)-2-fluoro-2-(Z)-propenyl) sulphonamide ethyl acetate
3-(3-cyano-phenyl)-2-fluoro-2-(Z)-propylene-1-alcohol (0.45g), N-(4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen) phenyl) sulphonamide ethyl acetate (1.12g) and triphenylphosphine (0.80g) are dissolved in the methylene dichloride (20ml), at ice-cooled lower dropping diethyl azodiformate (0.48ml), under same temperature, stirred 2 hours.With the reaction mixture concentrating under reduced pressure, residue is made with extra care (elutriant: dichloromethane/ethyl acetate=15/1), obtain colorless oil title compound 1.40g (yield 92%) with silica gel column chromatography.
1H?NMR(400MHz，CDCl 3)δppm：1.35(3H，t，J＝7.0)，1.47(9H，s)，1.74(2H，m)，1.90(2H，m)，3.34(2H，m)，3.68(2H，m)，4.00(2H，s)，4.30(2H，q，J＝7.0)，4.46(1H，m)，4.54(2H，d，J＝15.0)，5.62(1H，d，J＝36.5)，6.92(2H，d，J＝9.5)，7.42(3H，m)，7.51(1H，d，J＝7.0)，7.63(1H，d，J＝8.0)，7.71(1H，s)。
Reference example 119
The 2-Hydroxy M Phthalic Acid
2-methoxyl group m-phthalic acid (1.0g) is dissolved in 55% hydroiodic acid HI (10ml), stirs 1 hour at 80 ℃.Reaction mixture is poured in the frozen water, filtered and collect the throw out of separating out, obtain faint yellow solid title compound 0.9g (yield 95%).
1H?NMR(400MHz，DMSO-d 6)δppm：6.93(1H，t，J＝8.0)，7.96(2H，d，J＝8.0)。
Reference example 120
2-Hydroxy M Phthalic Acid dimethyl ester
2-Hydroxy M Phthalic Acid (1.9g) is dissolved in the methyl alcohol (20ml), in ice-cooled lower adding thionyl chloride (1.5ml), stirs 4 hours at 70 ℃.With the reaction mixture concentrating under reduced pressure, obtain white solid title compound 1.5g (yield 68%).
1H?NMR(500MHz，CDCl 3)δppm：3.96(6H，s)，6.94(1H，t，J＝8.0)，8.06(2H，d，J＝8.0)。
Reference example 121
2-hydroxyl-5-nitroisophthalic acid dimethyl ester
2-Hydroxy M Phthalic Acid dimethyl ester (1.5g) joined in the mixing solutions of 69% nitric acid (5ml) and the vitriol oil (5ml), ice-cooled lower stirring 0.5 hour.Reaction mixture is poured in the frozen water, used ethyl acetate extraction, extraction liquid is water and saturated common salt water washing successively, the organic layer anhydrous magnesium sulfate drying.Decompression steams solvent after filtering, and adds hexane in resulting yellow solid, obtains yellow solid title compound 1.6g (yield 89%) after the filtration.
1H?NMR(500MHz，CDCl 3)δppm：4.03(6H，s)，8.94(2H，s)。
Reference example 122
2-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-5-nitroisophthalic acid dimethyl ester
1-tertbutyloxycarbonyl-4-hydroxy piperidine (2.6g), 2-hydroxyl-5-nitroisophthalic acid dimethyl ester (1.6g) and triphenylphosphine (4.4g) are dissolved in the mixed solvent of methylene dichloride (40ml) and tetrahydrofuran (THF) (201m), add diethyl azodiformate (2.6ml), at room temperature stirred 4 hours.With the reaction mixture concentrating under reduced pressure, residue is made with extra care (elutriant: dichloromethane/ethyl acetate=19/1) with silica gel column chromatography, in the gained yellow solid, add hexane and ethyl acetate (4/1), obtain white solid title compound 2.2g (yield 78%) after the filtration.
1H?NMR(400MHz，CDCl 3)δppm：1.46(9H，s)，1.70-1.80(2H，m)，1.85-1.95(2H，m)，3.05(2H，m)，3.80-3.95(2H，m)，3.97(6H，s)，4.29(1H，m)，8.74(2H，s)。
Reference example 123
2-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-5-nitroisophthalic acid
2-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-5-nitroisophthalic acid dimethyl ester (10.7g) is dissolved in the concentrated hydrochloric acid (100ml), stirs 10 hours at 80 ℃.With the reaction mixture concentrating under reduced pressure, in residue, add hexane, filter and collect white solid.Then with the gained dissolution of solid in the mixed solvent of water (50ml) and acetone (50ml), at room temperature add sodium bicarbonate (4.6g) and tert-Butyl dicarbonate (5.9g), stirred 1 hour at 40 ℃.The saturated common salt water washing of reaction mixture ethyl acetate extraction, extraction liquid, the organic layer anhydrous magnesium sulfate drying.Decompression steams solvent after filtering, and adds hexane in residue, obtains faint yellow solid title compound 4.1g (yield 40%) after the filtration.
1H?NMR(500MHz，DMSO-d 6)δ?ppm：1.40(9H，s)，1.55-1.65(2H，m)，1.75-1.85(2H，m)，3.05-3.15(2H，m)，3.55-3.65(2H，m)，4.40(1H，m)，8.54(2H，s)。
Reference example 124
4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-3,5-diamino formyl radical oil of mirbane
2-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-5-nitroisophthalic acid (4.6g) is dissolved in the methylene dichloride (150ml), at ice-cooled lower adding isobutyl chlorocarbonate (4.3ml) and triethylamine (4.8ml), under same temperature, stirred 0.5 hour, then add 28% ammoniacal liquor (1.9ml), at room temperature stirred again 1 hour.Filter and collect the throw out of separating out, obtain faint yellow solid title compound 3.0g (yield 64%).
1H?NMR(500MHz，DMSO-d 6)δppm：1.40(9H，s)，1.60-1.70(2H，m)，1.75-1.85(2H，m)，3.05-3.15(2H，m)，3.55-3.65(2H，m)，4.48(1H，m)，8.31(2H，s)。
Reference example 125
4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-3,5-diamino formyl radical aniline
4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-3; 5-diamino formyl radical oil of mirbane (3.0g) is dissolved in the methyl alcohol (60ml); add palladium carbon catalyzer (0.3g); then in atmosphere of hydrogen, at room temperature stirred 1 hour; reaction mixture is filtered; filtrate decompression is concentrated, obtains yellow solid title compound 2.8g (quantitative yield).
1H?NMR(500MHz，CDCl 3)δppm：1.45(9H，s)，1.55-1.70(2H，m)，1.85-2.00(2H，m)，2.67(2H，m)，3.80-3.90(2H，m)，4.02(1H，m)，7.34(2H，s)。
Reference example 126
N-(4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-3,5-diamino formyl radical phenyl) sulphonamide ethyl acetate
4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-3; 5-diamino formyl radical aniline (2.8g) is dissolved in the methylene dichloride (80ml); add pyridine (1.4ml), then in ice-cooled lower dropping chlorine sulphonyl ethyl acetate (2.4ml), at room temperature stirred 2 hours.With the reaction mixture concentrating under reduced pressure, residue is made with extra care (elutriant: methylene chloride/methanol=4/1), obtain faint yellow solid title compound 0.9g (yield 23%) with silica gel column chromatography.
1H?NMR(500MHz，DMSO-d 6)δppm：1.18(3H，t，J＝7.0)，1.40(9H，s)，1.50-1.60(2H，m)，1.75-1.85(2H，m)，2.90-3.00(2H，m)，3.30(2H，s)，3.65-3.75(2H，m)，4.10(2H，q，J＝7.0)，4.15-4.20(1H，m)，7.43(2H，s)。
Reference example 127
N-(4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-3,5-diamino formyl radical phenyl)-N-(3-(3-cyano-phenyl)-2-(E)-propenyl) sulphonamide ethyl acetate
3-(3-cyano-phenyl)-2-(E)-propylene-1-alcohol (0.9g), N-(4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-3; 5-diamino formyl radical phenyl) sulphonamide ethyl acetate (0.9g) and triphenylphosphine (1.8g) are dissolved in the mixed solvent of methylene dichloride (30ml) and tetrahydrofuran (THF) (30ml); at ice-cooled lower adding diethyl azodiformate (1.1ml), then at room temperature stirred 1 hour.With the reaction mixture concentrating under reduced pressure, residue is made with extra care (elutriant: dichloromethane/ethyl acetate=1/2), obtain yellow amorphous solid title compound 0.8g (yield 73%) with silica gel column chromatography.
1H?NMR(500MHz，CDCl 3)δppm：1.26(3H，t，J＝7.0)，1.45(9H，s)，1.60-1.75(2H，m)，1.85-2.00(2H，m)，2.60-2.75(2H，m)，4.00-4.15(2H，m)，4.03(2H，s)，4.15-4.25(1H，m)，4.31(2H，q，J＝7.0)，4.55(2H，d，J＝7.0)，6.22(1H，dt，J＝16.0，7.0)，6.46(1H，d，J＝16.0)，7.35-7.45(2H，m)，7.50-7.60(3H，m)，8.16(1H，m)。
Reference example 128
4-methyl-5-nitro wintergreen oil
4-cresotinic acid (3.5g) is dissolved in the mixed solvent of methyl alcohol (8ml) and benzene (32ml), hexane solution (15.0ml) at ice-cooled lower adding 2.0M trimethyl silyl diazomethane then at room temperature stirred 0.5 hour.With the reaction mixture concentrating under reduced pressure, lower gained yellow oily material is joined in 69% nitric acid (20ml) ice-cooled, under same temperature, stirred 2 hours.Reaction mixture is poured in the frozen water, used ethyl acetate extraction, extraction liquid is water and saturated common salt water washing successively, the organic layer anhydrous magnesium sulfate drying.Decompression steams solvent after filtering, and residue is made with extra care (elutriant: hexane/ethyl acetate=4/1), obtain faint yellow solid title compound 1.3g (yield 21%) with silica gel column chromatography.
1H?NMR(500MHz，CDCl 3)δppm：2.66(3H，s)，4.01(3H，s)，6.92(1H，s)，8.66(1H，s)。
Reference example 129
4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-5-methoxycarbonyl-2-methyl oil of mirbane
1-tertbutyloxycarbonyl-4-hydroxy piperidine (5.4g), 4-methyl-5-nitro wintergreen oil (2.8g) and triphenylphosphine (9.0g) are dissolved in the methylene dichloride (100ml), add diethyl azodiformate (5.4ml), then at room temperature stirred 9 hours.With the reaction mixture concentrating under reduced pressure, residue is made with extra care (elutriant: hexane/ethyl acetate=4/1), obtain yellow oily title compound 4.9g (yield 93%) with silica gel column chromatography.
1H?NMR(400MHz，CDCl 3)δppm：1.47(9H，s)，1.85-1.95(4H，m)，2.68(3H，s)，3.50-3.65(4H，m)，3.91(3H，s)，4.78(1H，m)，6.84(1H，s)，8.63(1H，s)。
Reference example 130
4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-5-carboxyl-2-methyl oil of mirbane
4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-5-methoxycarbonyl-2-methyl oil of mirbane (4.9g) is dissolved in the concentrated hydrochloric acid (100ml), stirs 5 hours at 80 ℃.With the reaction mixture concentrating under reduced pressure, the gained white solid is dissolved in the mixed solvent of water (301m) and acetone (30ml), at room temperature adds sodium bicarbonate (2.3g) and tert-Butyl dicarbonate (3.3g), stirs 1 hour at 40 ℃.The saturated common salt water washing of reaction mixture ethyl acetate extraction, extraction liquid, the organic layer anhydrous magnesium sulfate drying.Decompression steams solvent after filtering, and obtains colourless amorphous solid title compound 4.8g (quantitative yield).
1H?NMR(500MHz，CDCl 3)δppm：1.48(9H，s)，1.85-1.95(2H，m)，2.05-2.15(2H，m)，2.71(3H，s)，3.35-3.45(2H，m)，3.70-3.80(2H，m)，4.85(1H，m)，6.93(1H，s)，8.84(1H，s)。
Reference example 131
4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-5-formamyl-2-methyl oil of mirbane
4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-5-carboxyl-2-methyl oil of mirbane (4.8g) is dissolved in methylene dichloride (100ml), at ice-cooled lower adding isobutyl chlorocarbonate (1.7ml) and triethylamine (1.8ml), under same temperature, stirred 1 hour, then add 28% ammoniacal liquor (0.8ml), restir 2 hours.With the reaction mixture concentrating under reduced pressure, residue is made with extra care (elutriant: methylene chloride/methanol=19/1), obtain white solid title compound 4.7g (yield 97%) with silica gel column chromatography.
1H?NMR(500MHz，DMSO-d 6)δppm：1.41(9H，s)，1.75-1.85(2H，m)，1.90-2.00(2H，m)，2.61(3H，s)，3.20-3.30(2H，m)，3.60-3.70(2H，m)，4.93(1H，m)，7.35(1H，s)，8.42(1H，s)。
Reference example 132
4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-5-formamyl-2-aminotoluene
4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-5-formamyl-2-methyl oil of mirbane (4.7g) is dissolved in the methyl alcohol (120ml); add palladium carbon catalyzer (0.5g); then in atmosphere of hydrogen, at room temperature stirred 2 hours; reaction mixture is filtered; filtrate decompression is concentrated, obtains yellow amorphous solid title compound 4.0g (yield 93%).
1H?NMR(500MHz，CDCl 3)δppm：1.47(9H，s)，1.65-1.75(2H，m)，1.95-2.05(2H，m)，2.20(3H，s)，3.18(2H，m)，3.75-3.85(2H，m)，4.45(1H，m)，6.74(1H，s)，7.47(1H，s)。
Reference example 133
N-(4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-5-formamyl-2-aminomethyl phenyl) sulphonamide ethyl acetate
4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-5-formamyl-2-aminotoluene (4.0g) is dissolved in the methylene dichloride (60ml); add pyridine (1.2ml); then in ice-cooled lower dropping chlorine sulphonyl ethyl acetate (1.9ml), at room temperature stirred 0.5 hour.With the reaction mixture concentrating under reduced pressure, residue is made with extra care (elutriant: methylene chloride/methanol=19/1), obtain faint yellow solid title compound 2.8g (yield 48%) with silica gel column chromatography.
1H?NMR(500MHz，CDCl 3)δppm：1.35(3H，t，J＝7.0)，1.48(9H，s)，1.75-1.85(2H，m)，2.00-2.10(2H，m)，2.49(3H，s)，3.29(2H，m)，3.75-3.85(2H，m)，4.06(2H，s)，4.33(2H，q，J＝7.0)，4.66(1H，m)，6.90(1H，s)，8.16(1H，s)。
Reference example 134
N-(4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-5-formamyl-2-aminomethyl phenyl)-N-(3-(3-cyano-phenyl)-2-(E)-propenyl) sulphonamide ethyl acetate
3-(3-cyano-phenyl)-2-(E)-propylene-1-alcohol (0.9g), N-(4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen)-5-formamyl-2-aminomethyl phenyl) sulphonamide ethyl acetate (2.8g) and triphenylphosphine (2.0g) are dissolved in the methylene dichloride (100ml); at ice-cooled lower adding diethyl azodiformate (1.2ml), then at room temperature stirred 3 hours.With the reaction mixture concentrating under reduced pressure, residue is made with extra care (elutriant: hexane/ethyl acetate=1/4), obtain yellow amorphous solid title compound 2.1g (yield 58%) with silica gel column chromatography.
1H?NMR(500MHz，CDCl 3)δppm：1.37(3H，t，J＝7.0)，1.47(9H，s)，1.75-1.85(2H，m)，2.00-2.10(2H，m)，2.41(3H，s)，3.25-3.35(2H，m)，3.75-3.85(2H，m)，4.02(1H，d，J＝14.0)，4.16(1H，d，J＝14.0)，4.20-4.25(1H，m)，4.30-4.40(2H，m)，4.65-4.75(2H，m)，6.20-6.30(1H，m)，6.35(1H，d，J＝16.0)，6.88(1H，s)，7.41(1H，m)，7.50-7.55(3H，m)，8.30(1H，s)。
Reference example 135
3-(5-cyano group-2-aminomethyl phenyl)-2-(E)-propylene-1-alcohol
In 1-t-butyldimethylsilyloxy base-2-propine (2.45g), add catecholborane (1.5ml), stirred 4 hours at 60 ℃.Reaction mixture is cooled to after the room temperature with toluene (40ml) dilution, then 20% ethanolic soln (5.0ml) that adds 3-bromo-4-aminomethyl phenyl nitrile (2.02g), tetrakis triphenylphosphine palladium title complex (0.58g) and sodium ethylate stirred 4 hours at 90 ℃.Add entry in reaction mixture, then use ethyl acetate extraction, extraction liquid is used 1M aqueous sodium hydroxide solution, water and saturated common salt water washing, organic layer anhydrous sodium sulfate drying successively.Decompression steams solvent, and residue is made with extra care (elutriant: hexane/ethyl acetate=8/1), obtain midbody compound (2.32g) with silica gel column chromatography.
Then, the midbody compound that obtains is dissolved in the tetrahydrofuran (THF) (60ml), then the tetrahydrofuran solution (12ml) at ice-cooled lower adding 1M tetrabutylammonium fluoride stirred 1 hour under same temperature.Add entry in reaction mixture, then with the methyl tertiary butyl ether extraction, extraction liquid is water and saturated common salt water washing successively, the organic layer anhydrous sodium sulfate drying.Decompression steams solvent, and residue is made with extra care (elutriant: hexane/ethyl acetate=3/2), obtain colorless solid title compound 0.64g (2 step yield 36%) with silica gel column chromatography.
1H?NMR(500MHz，CDCl 3)δppm：2.41(3H，s)，4.39(2H，bs)，6.30(1H，dt，J＝16.0，5.5)，6.80(1H，d，J＝16.0)，7.25(1H，d，J＝8.0)，7.43(1H，dd，J＝8.0，2.0)，7.70(1H，d，J＝2.0)。
Reference example 136
N-(4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen) phenyl)-N-(3-(5-cyano group-2-aminomethyl phenyl)-2-(E)-propenyl) sulphonamide ethyl acetate
3-(5-cyano group-2-aminomethyl phenyl)-2-(E)-propylene-1-alcohol (0.64g), N-(4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen) phenyl) sulphonamide ethyl acetate (1.62g) and triphenylphosphine (1.16g) are dissolved in the methylene dichloride (30ml), at ice-cooled lower dropping diethyl azodiformate (0.70ml), then under same temperature, stirred 2 hours.With the reaction mixture concentrating under reduced pressure, residue is made with extra care (elutriant: dichloromethane/ethyl acetate=12/1), obtain colourless amorphous solid title compound 2.03g (yield 92%) with silica gel column chromatography.
1H?NMR(500MHz，CDCl 3)δppm：1.36(3H，t，J＝7.0)，1.47(9H，s)，1.75(2H，m)，1.91(2H，m)，2.25(3H，s)，3.43(2H，m)，3.69(2H，m)，3.98(2H，s)，4.31(2H，q，J＝7.0)，4.47(1H，m)，4.49(2H，d，J＝6.5)，6.05(1H，dt，J＝15.5，6.5)，6.56(1H，d，J＝15.5)，6.92(2H，d，J＝10.0)，7.19(1H，d，J＝7.5)，7.40(3H，m)，7.55(1H，s)。
Reference example 137
3-(5-cyano group-2-fluorophenyl)-2-(E)-propylene-1-alcohol
In 1-t-butyldimethylsilyloxy base-2-propine (1.70g), add catecholborane (1.07ml), stirred 3 hours at 60 ℃.Reaction mixture is cooled to after the room temperature with toluene (20ml) dilution, then 20% ethanolic soln (3.4ml) that adds 3-bromo-4-fluorophenyl nitrile (1.4g), tetrakis triphenylphosphine palladium title complex (0.41g) and sodium ethylate stirred 6 hours at 100 ℃.Add the 1M aqueous sodium hydroxide solution in reaction mixture, then use extracted with diethyl ether, extraction liquid is used 1M aqueous sodium hydroxide solution, water and saturated common salt water washing, organic layer anhydrous sodium sulfate drying successively.Decompression steams solvent, and residue is made with extra care (elutriant: hexane/ethyl acetate=10/1), obtain midbody compound (1.29g) with silica gel column chromatography.
Then, the midbody compound that obtains is dissolved in the tetrahydrofuran (THF) (10ml), then the tetrahydrofuran solution (5.30ml) at ice-cooled lower adding 1M tetrabutylammonium fluoride stirred 1.5 hours under same temperature.Add entry in reaction mixture, then use ethyl acetate extraction, extraction liquid is water and saturated common salt water washing successively, the organic layer anhydrous magnesium sulfate drying.Decompression steams solvent, and residue is made with extra care (elutriant: hexane/ethyl acetate=1/1), obtain colorless solid title compound 0.46g (2 step yield 37%) with silica gel column chromatography.
1H?NMR(400MHz，CDCl 3)δppm：4.40(2H，m)，6.52(1H，dt，J＝16.5，5.0)，6.75(1H，d，J＝16.5)，7.16(1H，dd，J＝10.0，8.5)，7.53(1H，ddd，J＝8.5，5.0，2.0)，7.70(1H，dd，J＝7.0，2.0)。
Reference example 138
N-(4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen) phenyl)-N-(3-(5-cyano group-2-fluorophenyl)-2-(E)-propenyl) ethyl sulfonamide
3-(5-cyano group-2-fluorophenyl)-2-(E)-propylene-1-alcohol (0.72g), N-(4-(1-tertbutyloxycarbonyl piperidin-4-yl oxygen) phenyl) ethyl sulfonamide (1.63g) and triphenylphosphine (1.37g) are dissolved in the methylene dichloride (40ml), at ice-cooled lower dropping diethyl azodiformate (0.83ml), then at room temperature stirred 2 hours.With the reaction mixture concentrating under reduced pressure, residue is made with extra care (elutriant: dichloromethane/ethyl acetate=10/1), obtain colorless oil title compound 2.00g (yield 91%) with silica gel column chromatography.
1H?NMR(400MHz，CDCl 3)δppm：1.42(3H，t，J＝7.5)，1.47(9H，s)，1.74(2H，m)，1.90(2H，m)，3.06(2H，q，J＝7.5)，3.33(2H，m)，3.68(2H，m)，4.45(3H，m)，6.34(1H，dt，J＝16.0，6.0)，6.54(1H，d，J＝16.0)，6.90(2H，d，J＝9.0)，7.12(1H，dd，J＝10.5，9.0)，7.27(2H，d，J＝9.0)，7.51(1H，ddd，J＝9.0，5.0，2.0)，7.68(1H，dd，J＝6.5，2.0)。
Test example 1
The mensuration of anti-factor xa activity
The mensuration of anti-factor xa activity be according to people such as Hara method ( Thromb.Haemost, 71, 314 (1994)) slightly do to change and to carry out.The 50mM Tris hydrochloride buffer (pH 8.4) that will contain 0.9%NaCl, 0.4mM chromophoric substrate S-2222 (the first pharmaceutical chemicals company) and test compound mixes, the human factors Xa (Tokyo Cosmo Bio company limited) that adds 0.25 unit/ml makes the reaction beginning.In control group, replace test compound to join in the damping fluid with distilled water.Reaction soln (cumulative volume 0.1ml) was at room temperature hatched 5 minutes.Absorbancy with 96 hole titer plate readers (model 550, BioRad company) METHOD FOR CONTINUOUS DETERMINATION 405nm place calculates the increased value of 5 minutes internal absorbances as the index of factor xa activity.Concentration when the mensuration test compound suppresses 50% factor xa activity, i.e. IC 50Value is in order to the activity of the anti-factor Xa that estimates test compound.
The result shows, the benzamidine derivative shown in the above-mentioned general formula of the present invention (I) has excellent restraining effect to factor xa activity.Listed IC in the table 2 50Value is lower than the compound of 10nM, in addition, and the compd A of listing in the table represents the N-(4-(1-acetimidoyl-4-piperidines oxygen base) phenyl) of record among the WO98/31661 (EP976722)-N-(2-(3-amidino groups) phenoxy group) sulphonamide acetic acid dihydrochloride. (table 2)
It is active that embodiment compound number factor Xa suppresses
〔IC 50(nM)〕
Embodiment 3 8.6
Embodiment 4 6.4
Embodiment 8 4.5
Embodiment 9 7.4
Embodiment 10 4.6
Embodiment 11 8.1
Embodiment 22 8.3
Embodiment 23 8.3
Embodiment 28 9.0
Embodiment 29 9.0
Embodiment 31 10.0
Embodiment 34 10.0
Embodiment 36 7.1
Embodiment 38 8.7
Embodiment 41 7.5
Embodiment 46 6.8
Embodiment 47 3.7
Embodiment 49 9.8
Embodiment 54 4.6
Embodiment 55 5.0
Embodiment 56 10.0
Embodiment 57 9.3
Compd A 130
Test example 2
The mensuration of antitrypsic activity
The mensuration of antitrypsic activity be according to people such as Taniuchi method ( Thromb. Haemost., 79, 543 (1998)) slightly do to change and to carry out.50mM Tris hydrochloride buffer 85 μ l (pH 8.4), 5 μ l chromophoric substrate S-2222 (the total concn 0.4mM that will contain 0.9% sodium-chlor, the first pharmaceutical chemicals company) and test compound 5 μ l mix, add 5 μ l bovine trypsins (ultimate density 25 μ l albumen/ml, Sigma company), make the reaction beginning.In control group, replace test compound to join in the damping fluid with distilled water.Reaction soln (cumulative volume 0.1ml) is at room temperature hatched minute.Absorbancy with 96 hole droplet plate readers (model 550, BioRad company) METHOD FOR CONTINUOUS DETERMINATION 405nm place calculates the increased value of 5 minutes internal absorbances as the index of tryptic activity.Concentration when the mensuration test compound suppresses 50% tryptic activity, i.e. IC 50Value is in order to estimate the antitryptic activity of test compound.The results are shown in table 3 (table 3)
Embodiment compound number antitrypsic activity
〔IC 50(nM)〕
Embodiment 9 520
Embodiment 11 840
Formulation example 1
Hard capsule
The compound of the Powdered embodiment 9 of 50mg, 128.7mg lactose, 70mg Mierocrystalline cellulose and 1.3mg Magnesium Stearate are mixed, sieve by 60 eye mesh screens, in No. 3 gelatine capsules of then the 250mg powder being packed into, make capsule.
Formulation example 2
Tablet
Compound, 124mg lactose, 25mg Mierocrystalline cellulose and the 1mg Magnesium Stearate of the Powdered embodiment 9 of 50mg are mixed, use the tabletting machine compressing tablet, make the tablet of every 200mg.If necessary, can be to this tablet coating sugar-coat.
Formulation example 3
Injection
The compound of the embodiment 9 of 1.5 % by weight is stirred in the propylene glycol of 10 volume %.Be adjusted to prescribed volume with water for injection, then sterilize, make injection.
The possibility of utilizing on the industry
General formula of the present invention (I) compound and pharmaceutically acceptable salt thereof are owing to having excellent restraining effect to the activation blood coagulation X factor, and toxicity is low, so can be used as prophylactic agent or the curative (especially curative) of disorders of blood coagulation (such as cerebral infarction, myocardial infarction or the end thrombotic diseases such as cycle penalty slightly).
When general formula of the present invention (I) compound or its pharmaceutically acceptable salt during as the curative of above-mentioned disease or prophylactic agent, these compound or its salts can be individually dosed, or with the mixture of they and suitable pharmaceutically acceptable vehicle and thinner etc. with the formulations such as tablet, capsule, granule, pulvis or syrup by oral administration or with formulations such as injection or suppositorys by non-through enteral administration.
These formulations can be used various additives, press known method manufacturing such as vehicle, lubricant, binding agent, disintegrating agent, emulsifying agent, stablizer, drug flavoring and thinner etc.
Can enumerate carbohydrate derivatives such as lactose, white sugar, glucose, mannitol or Sorbitol Powder as the example of vehicle; The starch derivative such as W-Gum, yam starch, Alpha-starch or dextrin; The derivatived celluloses such as crystalline cellulose; Acacia; Dextran; The organic excipients such as amylopectin; And the silicate derivatives such as light anhydrous silicic acid, synthetic aluminium silicate, Calucium Silicate powder or metasilicic acid magnesium aluminate; The phosphoric acid salt such as calcium phosphate; The carbonate such as calcium carbonate; The inorganic excipients such as vitriol such as calcium sulfate.
Can enumerate Metallic stearates such as stearic acid, calcium stearate, Magnesium Stearate as the example of lubricant; Talcum powder; Colloid silica; The wax such as beeswax or spermaceti class; Boric acid; Hexanodioic acid; The vitriol such as sodium sulfate; Ethylene glycol; Fumaric acid; Sodium Benzoate; DL-Lys; The dodecyl sulfate such as sodium lauryl sulphate and Stepanol MG; The silicic acid such as silicic anhydride, hydrate of silicic acid class; And above-mentioned starch derivative.
Can enumerate for example hydroxypropylcellulose, Vltra tears, Polyvinylpyrolidone (PVP), polyoxyethylene glycol and the compound identical with above-mentioned vehicle as the example of binding agent.
Can enumerate the derivatived celluloses such as Xylo-Mucine of hydroxypropylcellulose, carboxymethyl cellulose, calcium carboxymethylcellulose and internal crosslinking such as low degree of substitution as the example of disintegrating agent; The farinose class of the chemical modifications such as carboxymethyl starch, sodium starch glycolate and cross-linking polyethylene pyrrolidone.
Can enumerate wilkinite and fillite isocolloid clay as the example of emulsifying agent; The metal hydroxides such as magnesium hydroxide and aluminium hydroxide; The cats products such as the anion surfactant such as sodium lauryl sulphate and calcium stearate, benzalkonium chloride; And the nonionogenic tensides such as Voranol EP 2001, polyoxyethylene sorbitan fatty acid esters and sucrose fatty ester.
Can enumerate such as methyl p-hydroxybenzoate with to parabenses such as Phenylbenzoic acid propyl ester as the example of stablizer; The alcohols such as butylene-chlorohydrin, phenylcarbinol and phenylethyl alcohol; Benzalkonium chloride; The phenol derivatives such as phenol and cresols; Thiomersal(ate); Dehydration acetic acid; And Sorbic Acid.
Can enumerate such as normally used sweeting agent, acidic flavoring agent and spices etc. as the example of drug flavoring.
The dosage of general formula of the present invention (I) compound and pharmaceutically acceptable salt thereof is according to factors such as patient's symptom and ages and different.During oral administration, suitable dosage is the at every turn lower 1mg (preferred 10mg) that is limited to of grownup, on be limited to 1000mg (preferably 500mg).During intravenous administration, suitable dosage is the at every turn lower 0.5mg (preferred 5mg) that is limited to of grownup, on be limited to 500mg (preferably 250mg), but according to patient's symptom, administration every day 1-6 time.

Claims (34)

1. acceptable salt on the benzamidine derivative shown in the general formula (I) or its pharmacology: In the formula:
R 1Represent hydrogen atom, halogen atom, C 1-C 6Alkyl or hydroxyl;
R 2Represent hydrogen atom, halogen atom or C 1-C 6Alkyl;
R 3Represent hydrogen atom; C 1-C 6Alkyl; By hydroxyl, carboxyl or (C 1-C 6Alkoxyl group) C of carbonyl substituted 1-C 6Alkyl; Group shown in the general formula (II) R in the formula 7Represent C 1-C 6Alkyl, m and n are identical or different, represent 1～6 integer; C 7-C 15Aralkyl; C 1-C 6Alkanoyl; Hydroxyl C 2-C 6Alkanoyl; C 1-C 6Alkyl sulphonyl; Or by (C 1-C 6Alkoxyl group) C of carbonyl or carboxyl substituted 1-C 6Alkyl sulphonyl;
R 4And R 5Identical or different, represent hydrogen atom, halogen atom, C 1-C 6Alkyl, halo C 1-C 6Alkyl, C 1-C 6Alkoxyl group, carboxyl, (C 1-C 6Alkoxyl group) carbonyl, formamyl, (C 1-C 6Alkyl) formamyl or two (C 1-C 6Alkyl) formamyl; And
R 6Represent 1-acetimidoyl pyrrolidin-3-yl or 1-acetimidoyl piperidin-4-yl.
2. according to acceptable salt, wherein R on the benzamidine derivative of claim 1 or its pharmacology 1Hydrogen atom, fluorine atom, chlorine atom, bromine atoms, C 1-C 4Alkyl or hydroxyl.
3. according to acceptable salt, wherein R on the benzamidine derivative of claim 1 or its pharmacology 1Hydrogen atom, fluorine atom, chlorine atom, methyl, ethyl or hydroxyl.
4. according to acceptable salt, wherein R on the benzamidine derivative of claim 1 or its pharmacology 1Hydrogen atom, fluorine atom, methyl or hydroxyl.
5. according to acceptable salt, wherein R on the benzamidine derivative of claim 1 or its pharmacology 1Hydrogen atom or hydroxyl.
According among the claim 1-5 any one benzamidine derivative or its pharmacology on acceptable salt, wherein R 2Hydrogen atom, fluorine atom, chlorine atom, bromine atoms or C 1-C 4Alkyl.
According among the claim 1-5 any one benzamidine derivative or its pharmacology on acceptable salt, wherein R 2Hydrogen atom, fluorine atom, chlorine atom, methyl or ethyl.
According among the claim 1-5 any one benzamidine derivative or its pharmacology on acceptable salt, wherein R 2Hydrogen atom, fluorine atom or methyl.
According among the claim 1-5 any one benzamidine derivative or its pharmacology on acceptable salt, wherein R 2Hydrogen atom or fluorine atom.
According among the claim 1-5 any one benzamidine derivative or its pharmacology on acceptable salt, wherein R 2It is hydrogen atom.
11. according among the claim 1-10 any one benzamidine derivative or its pharmacology on acceptable salt, wherein R 3Hydrogen atom, C 1-C 4Alkyl; Hydroxyl C 1-C 4Alkyl; Carboxyl C 1-C 4Alkyl or (C 1-C 4Alkoxyl group) carbonyl (C 1-C 4) alkyl; Group shown in the general formula (II): R in the formula 7Represent C 1-C 4Alkyl, m and n are identical or different, represent the integer of 1-4; Benzyl, menaphthyl, diphenyl methyl or styroyl; C 1-C 4Alkanoyl; Hydroxyacetyl, 3-hydroxyl propionyl or 4-maloyl group; Methylsulfonyl, ethylsulfonyl, the third alkylsulfonyl, fourth alkylsulfonyl, penta alkylsulfonyl or own alkylsulfonyl; Or by (C 1-C 4Alkoxyl group) C of carbonyl or carboxyl substituted 1-C 4Alkyl sulphonyl.
12. according among the claim 1-10 any one benzamidine derivative or its pharmacology on acceptable salt, wherein R 3It is hydrogen atom; C 1-C 4Alkyl; 2-hydroxyethyl, carboxymethyl, methoxycarbonyl methyl, ethoxycarbonylmethyl group, the third oxygen carbonyl methyl or butoxy carbonyl methyl; Group shown in the general formula (II): R in the formula 7Represent methylidene or ethyl, m and n are identical or different, represent 1 or 2 integer; Benzyl or styroyl; Formyl radical or ethanoyl; Hydroxyacetyl; Methylsulfonyl, ethylsulfonyl or fourth alkylsulfonyl; Or by (C 1-C 4Alkoxyl group) methylsulfonyl of carbonyl or carboxyl substituted or ethylsulfonyl.
13. according among the claim 1-10 any one benzamidine derivative or its pharmacology on acceptable salt, wherein R 3Hydrogen atom, methyl, ethyl, sec.-propyl, 2-hydroxyethyl, carboxymethyl, methoxycarbonyl methyl, ethoxycarbonylmethyl group, the third oxygen carbonyl methyl, butoxy carbonyl methyl, ethanoyl, hydroxyacetyl, methylsulfonyl, ethylsulfonyl, fourth alkylsulfonyl, methoxycarbonyl methylsulfonyl, ethoxycarbonyl methylsulfonyl, carboxyl methylsulfonyl, 2-methoxycarbonyl ethylsulfonyl, 2-ethoxycarbonyl ethylsulfonyl or 2-carboxyl ethylsulfonyl.
14. according among the claim 1-10 any one benzamidine derivative or its pharmacology on acceptable salt, wherein R 3Sec.-propyl, 2-hydroxyethyl, carboxymethyl, methoxycarbonyl methyl, ethoxycarbonylmethyl group, ethylsulfonyl, methoxycarbonyl methylsulfonyl, ethoxycarbonyl methylsulfonyl, carboxyl methylsulfonyl, 2-methoxycarbonyl ethylsulfonyl, 2-ethoxycarbonyl ethylsulfonyl or 2-carboxyl ethylsulfonyl.
15. according among the claim 1-10 any one benzamidine derivative or its pharmacology on acceptable salt, wherein R 3Sec.-propyl, carboxymethyl, ethoxycarbonylmethyl group, ethoxycarbonyl methylsulfonyl or carboxyl methylsulfonyl.
16. according among the claim 1-10 any one benzamidine derivative or its pharmacology on acceptable salt, wherein R 3Ethoxycarbonyl methylsulfonyl or carboxyl methylsulfonyl.
17. according among the claim 1-16 any one benzamidine derivative or its pharmacology on acceptable salt, wherein R 4And R 5Identical or different, each represents hydrogen atom, fluorine atom, chlorine atom, bromine atoms, C 1-C 4Alkyl, methyl fluoride, difluoromethyl, trifluoromethyl, 2-fluoro ethyl, 2,2-two fluoro ethyls, 2,2,2-trifluoroethyl, C 1-C 4Alkoxyl group, carboxyl, methoxycarbonyl, ethoxycarbonyl, formamyl, methylamino formyl radical or N, the N-formyl-dimethylamino.
18. according among the claim 1-16 any one benzamidine derivative or its pharmacology on acceptable salt, wherein R 4Hydrogen atom, fluorine atom, chlorine atom or trifluoromethyl,
R 5Hydrogen atom, fluorine atom, chlorine atom, bromine atoms, C 1-C 4Alkyl, methyl fluoride, difluoromethyl, trifluoromethyl, 2-fluoro ethyl, 2,2-two fluoro ethyls, 2,2,2-trifluoroethyl, C 1-C 4Alkoxyl group, carboxyl, methoxycarbonyl, ethoxycarbonyl, formamyl, methylamino formyl radical or N, the N-formyl-dimethylamino.
19. according among the claim 1-16 any one benzamidine derivative or its pharmacology on acceptable salt, wherein R 4Hydrogen atom, fluorine atom or chlorine atom,
R 5Hydrogen atom, fluorine atom, chlorine atom, bromine atoms, methyl, ethyl, trifluoromethyl, methoxyl group, oxyethyl group or formamyl.
20. according among the claim 1-16 any one benzamidine derivative or its pharmacology on acceptable salt, wherein R 4Hydrogen atom,
R 5Hydrogen atom, fluorine atom, chlorine atom, methyl, trifluoromethyl or formamyl.
21. according among the claim 1-16 any one benzamidine derivative or its pharmacology on acceptable salt, wherein R 4Hydrogen atom,
R 5Hydrogen atom, chlorine atom, methyl or formamyl.
22. according among the claim 1-21 any one benzamidine derivative or its pharmacology on acceptable salt, wherein R 6It is 1-acetimidoyl piperidin-4-yl.
23. be selected from following compounds according to acceptable salt on the benzamidine derivative of claim 1 or its pharmacology:
N-(4-(1-acetimidoyl piperidin-4-yl oxygen) phenyl)-N-(3-(3-carbamimido-phenyl)-2-(E) propenyl) sulphonamide ethyl acetate,
N-(4-(1-acetimidoyl piperidin-4-yl oxygen)-3-chloro-phenyl-)-N-(3-(3-carbamimido-phenyl)-2-(E) propenyl) sulphonamide ethyl acetate,
N-(4-(1-acetimidoyl piperidin-4-yl oxygen)-3-aminomethyl phenyl)-N-(3-(3-carbamimido-phenyl)-2-(E) propenyl) sulphonamide ethyl acetate,
N-(4-(1-acetimidoyl piperidin-4-yl oxygen)-3-formamyl phenyl)-N-(3-(3-carbamimido-phenyl)-2-(E) propenyl) sulphonamide ethyl acetate,
N-(4-(1-acetimidoyl piperidin-4-yl oxygen) phenyl)-N-(3-(3-carbamimido-phenyl)-2-(E) propenyl) sulphonamide acetic acid,
N-(4-(1-acetimidoyl piperidin-4-yl oxygen)-3-fluorophenyl)-N-(3-(3-carbamimido-phenyl)-2-(E) propenyl) sulphonamide acetic acid,
N-(4-(1-acetimidoyl piperidin-4-yl oxygen)-3-chloro-phenyl-)-N-(3-(3-carbamimido-phenyl)-2-(E) propenyl) sulphonamide acetic acid,
N-(4-(1-acetimidoyl piperidin-4-yl oxygen)-3-aminomethyl phenyl)-N-(3-(3-carbamimido-phenyl)-2-(E) propenyl) sulphonamide acetic acid,
N-(4-(1-acetimidoyl piperidin-4-yl oxygen)-3-trifluoromethyl)-N-(3-(3-carbamimido-phenyl)-2-(E) propenyl) sulphonamide acetic acid,
N-(4-(1-acetimidoyl piperidin-4-yl oxygen)-3-formamyl phenyl)-N-(3-(3-carbamimido-phenyl)-2-(E) propenyl) sulphonamide acetic acid,
N-(4-(1-acetimidoyl piperidin-4-yl oxygen)-3,5-dichlorophenyl)-N-(3-(3-carbamimido-phenyl)-2-(E) propenyl) sulphonamide ethyl acetate,
N-(4-(1-acetimidoyl piperidin-4-yl oxygen)-3,5-dichlorophenyl)-N-(3-(3-carbamimido-phenyl)-2-(E) propenyl) sulphonamide acetic acid, and
N-(4-(1-acetimidoyl piperidin-4-yl oxygen)-N-(3-(3-carbamimido-phenyl)-2-fluoro-2-(E)-propenyl) sulphonamide acetic acid.
24. contain the treatment significant quantity according among the claim 1-23 any one benzamidine derivative or its pharmacology on the pharmaceutical composition of acceptable salt.
25. be used for prevention or treatment disorders of blood coagulation contain the treatment significant quantity according to claim 1-23 any one benzamidine derivative or its pharmacology on the pharmaceutical composition of acceptable salt.
26. be used for prevention or treatment thrombotic diseases contain the treatment significant quantity according to claim 1-23 any one benzamidine derivative or its pharmacology on the pharmaceutical composition of acceptable salt.
27. be used for prevention or treatment cerebral infarction contain the treatment significant quantity according to claim 1-23 any one benzamidine derivative or its pharmacology on the pharmaceutical composition of acceptable salt.
28. be used for prevention or treatment myocardial infarction contain the treatment significant quantity according to claim 1-23 any one benzamidine derivative or its pharmacology on the pharmaceutical composition of acceptable salt.
29. be used for prevention or treatment peripheral circulation disorders contain the treatment significant quantity according to claim 1-23 any one benzamidine derivative or its pharmacology on the pharmaceutical composition of acceptable salt.
30. according among the claim 1-23 any one benzamidine derivative or its pharmacology on acceptable salt for the manufacture of the prevention of disorders of blood coagulation or the purposes of curative.
31. according among the claim 1-23 any one benzamidine derivative or its pharmacology on acceptable salt for the manufacture of the prevention of thrombotic diseases or the purposes of curative.
32. according among the claim 1-23 any one benzamidine derivative or its pharmacology on acceptable salt for the manufacture of the prevention of cerebral infarction or the purposes of curative.
33. according among the claim 1-23 any one benzamidine derivative or its pharmacology on acceptable salt for the manufacture of the prevention of myocardial infarction or the purposes of curative.
34. according among the claim 1-23 any one benzamidine derivative or its pharmacology on acceptable salt for the manufacture of the end slightly prevention of cycle penalty or the purposes of curative.
CNB008178003A 1999-10-28 2000-10-25 Benzamidine derivatives Expired - Fee Related CN1293052C (en)

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